Trial Outcomes & Findings for Pharmacokinetics of Midazolam, Dabigatran, Pitavastatin, Atorvastatin, and Rosuvastatin in Participants With Renal Insufficiency in the Presence and Absence of Rifampin (MK-0000-386) (NCT NCT03311841)
NCT ID: NCT03311841
Last Updated: 2020-01-09
Results Overview
AUC0-inf is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease (ESRD) requiring hemodialysis.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
32 participants
Primary outcome timeframe
0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
Results posted on
2020-01-09
Participant Flow
Participant milestones
| Measure |
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Mild Impairment
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Period 1
STARTED
|
6
|
7
|
6
|
7
|
6
|
|
Period 1
COMPLETED
|
6
|
7
|
6
|
7
|
6
|
|
Period 1
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
|
14-day Wash-out
STARTED
|
6
|
7
|
6
|
7
|
6
|
|
14-day Wash-out
COMPLETED
|
6
|
6
|
6
|
6
|
6
|
|
14-day Wash-out
NOT COMPLETED
|
0
|
1
|
0
|
1
|
0
|
|
Period 2
STARTED
|
6
|
6
|
6
|
6
|
6
|
|
Period 2
COMPLETED
|
6
|
6
|
6
|
6
|
6
|
|
Period 2
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
Reasons for withdrawal
| Measure |
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Mild Impairment
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
14-day Wash-out
Adverse Event
|
0
|
1
|
0
|
0
|
0
|
|
14-day Wash-out
Non-Compliance With Study Drug
|
0
|
0
|
0
|
1
|
0
|
Baseline Characteristics
Pharmacokinetics of Midazolam, Dabigatran, Pitavastatin, Atorvastatin, and Rosuvastatin in Participants With Renal Insufficiency in the Presence and Absence of Rifampin (MK-0000-386)
Baseline characteristics by cohort
| Measure |
End-Stage Renal Disease
n=6 Participants
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=7 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Mild Impairment
n=7 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Total
n=32 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|---|
|
Age, Continuous
|
56.7 Years
STANDARD_DEVIATION 8.04 • n=99 Participants
|
64.9 Years
STANDARD_DEVIATION 7.10 • n=107 Participants
|
67.0 Years
STANDARD_DEVIATION 11.19 • n=206 Participants
|
65.4 Years
STANDARD_DEVIATION 8.90 • n=7 Participants
|
57.8 Years
STANDARD_DEVIATION 7.88 • n=31 Participants
|
62.5 Years
STANDARD_DEVIATION 9.15 • n=30 Participants
|
|
Sex: Female, Male
Female
|
0 Participants
n=99 Participants
|
1 Participants
n=107 Participants
|
4 Participants
n=206 Participants
|
3 Participants
n=7 Participants
|
3 Participants
n=31 Participants
|
11 Participants
n=30 Participants
|
|
Sex: Female, Male
Male
|
6 Participants
n=99 Participants
|
6 Participants
n=107 Participants
|
2 Participants
n=206 Participants
|
4 Participants
n=7 Participants
|
3 Participants
n=31 Participants
|
21 Participants
n=30 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
0 Participants
n=99 Participants
|
5 Participants
n=107 Participants
|
4 Participants
n=206 Participants
|
5 Participants
n=7 Participants
|
6 Participants
n=31 Participants
|
20 Participants
n=30 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
6 Participants
n=99 Participants
|
2 Participants
n=107 Participants
|
2 Participants
n=206 Participants
|
2 Participants
n=7 Participants
|
0 Participants
n=31 Participants
|
12 Participants
n=30 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=31 Participants
|
0 Participants
n=30 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
1 Participants
n=7 Participants
|
0 Participants
n=31 Participants
|
1 Participants
n=30 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
00 Participants
n=206 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=31 Participants
|
0 Participants
n=30 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=31 Participants
|
0 Participants
n=30 Participants
|
|
Race (NIH/OMB)
Black or African American
|
6 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
3 Participants
n=7 Participants
|
0 Participants
n=31 Participants
|
9 Participants
n=30 Participants
|
|
Race (NIH/OMB)
White
|
0 Participants
n=99 Participants
|
7 Participants
n=107 Participants
|
6 Participants
n=206 Participants
|
3 Participants
n=7 Participants
|
6 Participants
n=31 Participants
|
22 Participants
n=30 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=31 Participants
|
0 Participants
n=30 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=31 Participants
|
0 Participants
n=30 Participants
|
PRIMARY outcome
Timeframe: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dosePopulation: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-inf for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
AUC0-inf is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease (ESRD) requiring hemodialysis.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
n=6 Participants
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=7 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1
Midazolam
|
176 pg*hr/mL
Interval 119.0 to 259.0
|
273 pg*hr/mL
Interval 185.0 to 403.0
|
110 pg*hr/mL
Interval 74.6 to 162.0
|
260 pg*hr/mL
Interval 181.0 to 372.0
|
364 pg*hr/mL
Interval 247.0 to 537.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1
Dabigatran
|
1610 pg*hr/mL
Interval 1020.0 to 2530.0
|
1580 pg*hr/mL
Interval 1010.0 to 2500.0
|
5370 pg*hr/mL
Interval 3410.0 to 8460.0
|
7900 pg*hr/mL
Interval 5010.0 to 12400.0
|
4550 pg*hr/mL
Interval 2890.0 to 7180.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1
Pitavastatin
|
688 pg*hr/mL
Interval 464.0 to 1020.0
|
520 pg*hr/mL
Interval 350.0 to 771.0
|
676 pg*hr/mL
Interval 456.0 to 1000.0
|
648 pg*hr/mL
Interval 450.0 to 933.0
|
1020 pg*hr/mL
Interval 686.0 to 1510.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1
Pitavastatin lactone (metabolite)
|
1610 pg*hr/mL
Interval 1140.0 to 2290.0
|
1540 pg*hr/mL
Interval 1090.0 to 2190.0
|
1100 pg*hr/mL
Interval 774.0 to 1560.0
|
1680 pg*hr/mL
Interval 1220.0 to 2320.0
|
2240 pg*hr/mL
Interval 1580.0 to 3170.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1
Atorvastatin
|
329 pg*hr/mL
Interval 183.0 to 593.0
|
292 pg*hr/mL
Interval 180.0 to 472.0
|
329 pg*hr/mL
Interval 203.0 to 531.0
|
476 pg*hr/mL
Interval 305.0 to 743.0
|
511 pg*hr/mL
Interval 316.0 to 826.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1
Ortho-hydroxyatorvastatin (metabolite)
|
286 pg*hr/mL
Interval 181.0 to 453.0
|
208 pg*hr/mL
Interval 143.0 to 302.0
|
163 pg*hr/mL
Interval 112.0 to 237.0
|
226 pg*hr/mL
Interval 160.0 to 319.0
|
273 pg*hr/mL
Interval 181.0 to 411.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1
Rosuvastatin
|
262 pg*hr/mL
Interval 136.0 to 505.0
|
292 pg*hr/mL
Interval 137.0 to 624.0
|
208 pg*hr/mL
Interval 116.0 to 374.0
|
365 pg*hr/mL
Interval 213.0 to 624.0
|
575 pg*hr/mL
Interval 319.0 to 1030.0
|
PRIMARY outcome
Timeframe: Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dosePopulation: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-inf for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
To evaluate the effect of a single oral dose of rifampin on the AUC0-inf of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. AUC0-inf is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include data from the end-stage renal disease participants as they did not receive rifampin during Period 2.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=6 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Effect of Rifampin on AUC0-inf Post-dose Period 2
Midazolam
|
189 pg*hr/mL
Interval 132.0 to 269.0
|
239 pg*hr/mL
Interval 168.0 to 341.0
|
—
|
244 pg*hr/mL
Interval 175.0 to 340.0
|
359 pg*hr/mL
Interval 252.0 to 512.0
|
|
Effect of Rifampin on AUC0-inf Post-dose Period 2
Dabigatran
|
3040 pg*hr/mL
Interval 2090.0 to 4400.0
|
3290 pg*hr/mL
Interval 2270.0 to 4770.0
|
—
|
10700 pg*hr/mL
Interval 7390.0 to 15600.0
|
7240 pg*hr/mL
Interval 4990.0 to 10500.0
|
|
Effect of Rifampin on AUC0-inf Post-dose Period 2
Pitavastatin
|
2530 pg*hr/mL
Interval 1590.0 to 4030.0
|
1910 pg*hr/mL
Interval 1200.0 to 3030.0
|
—
|
2850 pg*hr/mL
Interval 1840.0 to 4440.0
|
3500 pg*hr/mL
Interval 2200.0 to 5570.0
|
|
Effect of Rifampin on AUC0-inf Post-dose Period 2
Pitavastatin lactone (metabolite)
|
1930 pg*hr/mL
Interval 1410.0 to 2640.0
|
1340 pg*hr/mL
Interval 981.0 to 1840.0
|
—
|
1560 pg*hr/mL
Interval 1160.0 to 2100.0
|
2500 pg*hr/mL
Interval 1830.0 to 3430.0
|
|
Effect of Rifampin on AUC0-inf Post-dose Period 2
Atorvastatin
|
1710 pg*hr/mL
Interval 1040.0 to 2810.0
|
1770 pg*hr/mL
Interval 1180.0 to 2660.0
|
—
|
2240 pg*hr/mL
Interval 1520.0 to 3320.0
|
2430 pg*hr/mL
Interval 1620.0 to 3650.0
|
|
Effect of Rifampin on AUC0-inf Post-dose Period 2
Ortho-hydroxyatorvastatin (metabolite)
|
1760 pg*hr/mL
Interval 1060.0 to 2940.0
|
1650 pg*hr/mL
Interval 1080.0 to 2500.0
|
—
|
1620 pg*hr/mL
Interval 1080.0 to 2430.0
|
1870 pg*hr/mL
Interval 1230.0 to 2840.0
|
|
Effect of Rifampin on AUC0-inf Post-dose Period 2
Rosuvastatin
|
1060 pg*hr/mL
Interval 695.0 to 1620.0
|
830 pg*hr/mL
Interval 553.0 to 1250.0
|
—
|
1240 pg*hr/mL
Interval 839.0 to 1830.0
|
1800 pg*hr/mL
Interval 1150.0 to 2820.0
|
PRIMARY outcome
Timeframe: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dosePopulation: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-24 for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post-dose. This is a measure of the average amount of study drug in the blood plasma over a period of 24 hours after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
n=6 Participants
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=7 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1
Rosuvastatin
|
191 pg*hr/mL
Interval 109.0 to 334.0
|
153 pg*hr/mL
Interval 91.6 to 255.0
|
162 pg*hr/mL
Interval 97.2 to 271.0
|
223 pg*hr/mL
Interval 139.0 to 358.0
|
343 pg*hr/mL
Interval 206.0 to 573.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1
Midazolam
|
168 pg*hr/mL
Interval 117.0 to 240.0
|
252 pg*hr/mL
Interval 176.0 to 360.0
|
106 pg*hr/mL
Interval 74.2 to 152.0
|
235 pg*hr/mL
Interval 169.0 to 328.0
|
317 pg*hr/mL
Interval 222.0 to 454.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1
Dabigatran
|
1380 pg*hr/mL
Interval 907.0 to 2100.0
|
1440 pg*hr/mL
Interval 949.0 to 2200.0
|
2100 pg*hr/mL
Interval 1380.0 to 3200.0
|
4470 pg*hr/mL
Interval 3030.0 to 6590.0
|
3440 pg*hr/mL
Interval 2260.0 to 5240.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1
Pitavastatin
|
543 pg*hr/mL
Interval 376.0 to 783.0
|
415 pg*hr/mL
Interval 288.0 to 600.0
|
593 pg*hr/mL
Interval 411.0 to 857.0
|
525 pg*hr/mL
Interval 374.0 to 738.0
|
764 pg*hr/mL
Interval 529.0 to 1100.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1
Pitavastatin lactone (metabolite)
|
1040 pg*hr/mL
Interval 772.0 to 1390.0
|
1010 pg*hr/mL
Interval 750.0 to 1350.0
|
858 pg*hr/mL
Interval 639.0 to 1150.0
|
1100 pg*hr/mL
Interval 835.0 to 1440.0
|
1280 pg*hr/mL
Interval 950.0 to 1710.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1
Atorvastatin
|
219 pg*hr/mL
Interval 128.0 to 377.0
|
198 pg*hr/mL
Interval 127.0 to 308.0
|
287 pg*hr/mL
Interval 184.0 to 446.0
|
300 pg*hr/mL
Interval 199.0 to 452.0
|
329 pg*hr/mL
Interval 211.0 to 512.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1
Ortho-hydroxyatorvastatin (metabolite)
|
139 pg*hr/mL
Interval 86.9 to 221.0
|
108 pg*hr/mL
Interval 73.8 to 158.0
|
115 pg*hr/mL
Interval 78.3 to 168.0
|
112 pg*hr/mL
Interval 78.5 to 159.0
|
143 pg*hr/mL
Interval 98.0 to 210.0
|
PRIMARY outcome
Timeframe: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dosePopulation: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-last for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
AUC0-last is the area under the plasma concentration-time curve from time zero to time of last measurable concentration. This is a measure of the amount of study drug in the blood plasma from pre-dose until the last measurable concentration of study drug could be determined. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
n=6 Participants
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=7 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1
Midazolam
|
167 pg*hr/mL
Interval 113.0 to 248.0
|
264 pg*hr/mL
Interval 178.0 to 392.0
|
105 pg*hr/mL
Interval 70.8 to 156.0
|
248 pg*hr/mL
Interval 172.0 to 358.0
|
344 pg*hr/mL
Interval 232.0 to 511.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1
Dabigatran
|
1440 pg*hr/mL
Interval 910.0 to 2270.0
|
1410 pg*hr/mL
Interval 891.0 to 2230.0
|
3740 pg*hr/mL
Interval 2370.0 to 5910.0
|
7450 pg*hr/mL
Interval 4870.0 to 11400.0
|
4230 pg*hr/mL
Interval 2680.0 to 6690.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1
Pitavastatin
|
643 pg*hr/mL
Interval 431.0 to 959.0
|
483 pg*hr/mL
Interval 324.0 to 721.0
|
649 pg*hr/mL
Interval 435.0 to 968.0
|
602 pg*hr/mL
Interval 416.0 to 871.0
|
950 pg*hr/mL
Interval 637.0 to 1420.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1
Pitavastatin lactone (metabolite)
|
1490 pg*hr/mL
Interval 1060.0 to 2080.0
|
1450 pg*hr/mL
Interval 1030.0 to 2030.0
|
1060 pg*hr/mL
Interval 754.0 to 1480.0
|
1570 pg*hr/mL
Interval 1150.0 to 2140.0
|
2020 pg*hr/mL
Interval 1440.0 to 2830.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1
Atorvastatin
|
295 pg*hr/mL
Interval 161.0 to 539.0
|
255 pg*hr/mL
Interval 155.0 to 417.0
|
298 pg*hr/mL
Interval 182.0 to 488.0
|
419 pg*hr/mL
Interval 266.0 to 662.0
|
459 pg*hr/mL
Interval 280.0 to 751.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1
Ortho-hydroxyatorvastatin (metabolite)
|
221 pg*hr/mL
Interval 127.0 to 385.0
|
152 pg*hr/mL
Interval 96.8 to 239.0
|
126 pg*hr/mL
Interval 80.3 to 198.0
|
176 pg*hr/mL
Interval 116.0 to 267.0
|
256 pg*hr/mL
Interval 163.0 to 402.0
|
|
Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1
Rosuvastatin
|
231 pg*hr/mL
Interval 125.0 to 424.0
|
181 pg*hr/mL
Interval 104.0 to 315.0
|
171 pg*hr/mL
Interval 98.0 to 298.0
|
269 pg*hr/mL
Interval 161.0 to 451.0
|
479 pg*hr/mL
Interval 274.0 to 835.0
|
PRIMARY outcome
Timeframe: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dosePopulation: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Cmax for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
Cmax is the peak plasma concentration of study drug after administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
n=6 Participants
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=7 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Maximum Plasma Concentration (Cmax) Post-dose Period 1
Midazolam
|
70.7 pg/mL
Interval 52.3 to 95.5
|
73.2 pg/mL
Interval 54.1 to 98.8
|
39.9 pg/mL
Interval 29.5 to 53.9
|
68.4 pg/mL
Interval 51.8 to 90.4
|
77.2 pg/mL
Interval 57.1 to 104.0
|
|
Maximum Plasma Concentration (Cmax) Post-dose Period 1
Dabigatran
|
153 pg/mL
Interval 96.9 to 243.0
|
183 pg/mL
Interval 115.0 to 290.0
|
132 pg/mL
Interval 83.1 to 208.0
|
319 pg/mL
Interval 209.0 to 489.0
|
312 pg/mL
Interval 197.0 to 494.0
|
|
Maximum Plasma Concentration (Cmax) Post-dose Period 1
Pitavastatin
|
244 pg/mL
Interval 174.0 to 342.0
|
164 pg/mL
Interval 117.0 to 230.0
|
242 pg/mL
Interval 173.0 to 339.0
|
218 pg/mL
Interval 160.0 to 299.0
|
303 pg/mL
Interval 216.0 to 425.0
|
|
Maximum Plasma Concentration (Cmax) Post-dose Period 1
Pitavastatin lactone (metabolite)
|
105 pg/mL
Interval 79.9 to 137.0
|
88.1 pg/mL
Interval 67.1 to 116.0
|
78.5 pg/mL
Interval 59.8 to 103.0
|
95.4 pg/mL
Interval 74.2 to 123.0
|
106 pg/mL
Interval 80.6 to 139.0
|
|
Maximum Plasma Concentration (Cmax) Post-dose Period 1
Atorvastatin
|
31.9 pg/mL
Interval 15.5 to 65.7
|
21.6 pg/mL
Interval 12.0 to 38.9
|
63.7 pg/mL
Interval 35.3 to 115.0
|
46.7 pg/mL
Interval 27.1 to 80.5
|
55.0 pg/mL
Interval 30.5 to 99.1
|
|
Maximum Plasma Concentration (Cmax) Post-dose Period 1
Ortho-hydroxyatorvastatin (metabolite)
|
8.50 pg/mL
Interval 5.23 to 13.8
|
7.67 pg/mL
Interval 5.16 to 11.4
|
8.58 pg/mL
Interval 5.77 to 12.8
|
7.22 pg/mL
Interval 5.0 to 10.4
|
9.50 pg/mL
Interval 6.39 to 14.1
|
|
Maximum Plasma Concentration (Cmax) Post-dose Period 1
Rosuvastatin
|
23.6 pg/mL
Interval 12.4 to 45.1
|
21.5 pg/mL
Interval 11.9 to 38.9
|
22.5 pg/mL
Interval 12.4 to 40.6
|
24.4 pg/mL
Interval 14.1 to 42.1
|
40.4 pg/mL
Interval 22.4 to 72.9
|
PRIMARY outcome
Timeframe: 24 hours post-dosePopulation: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of C24 for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
C24hr is a measure of the plasma study drug concentration 24 hours post-dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
n=6 Participants
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=7 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Plasma Concentration at 24 Hours (C24) Post-dose Period 1
Ortho-hydroxyatorvastatin (metabolite)
|
5.02 pg/mL
Interval 2.26 to 9.31
|
3.08 pg/mL
Interval 2.1 to 4.51
|
3.67 pg/mL
Interval 0.0 to 4.64
|
3.25 pg/mL
Interval 2.29 to 4.63
|
4.43 pg/mL
Interval 3.03 to 6.49
|
|
Plasma Concentration at 24 Hours (C24) Post-dose Period 1
Rosuvastatin
|
3.59 pg/mL
Interval 2.19 to 5.88
|
1.94 pg/mL
Interval 1.24 to 3.05
|
2.64 pg/mL
Interval 0.0 to 4.36
|
3.40 pg/mL
Interval 2.24 to 5.16
|
6.01 pg/mL
Interval 3.83 to 9.43
|
|
Plasma Concentration at 24 Hours (C24) Post-dose Period 1
Midazolam
|
0.734 pg/mL
Interval 0.0 to 1.06
|
1.57 pg/mL
Interval 0.914 to 2.7
|
0.283 pg/mL
Interval 0.0 to 0.928
|
1.83 pg/mL
Interval 0.0 to 8.47
|
2.64 pg/mL
Interval 1.54 to 4.54
|
|
Plasma Concentration at 24 Hours (C24) Post-dose Period 1
Dabigatran
|
18.7 pg/mL
Interval 12.1 to 28.9
|
7.70 pg/mL
Interval 0.0 to 26.6
|
70.2 pg/mL
Interval 45.3 to 109.0
|
107 pg/mL
Interval 71.7 to 161.0
|
59.3 pg/mL
Interval 38.3 to 91.8
|
|
Plasma Concentration at 24 Hours (C24) Post-dose Period 1
Pitavastatin
|
5.32 pg/mL
Interval 3.62 to 7.82
|
4.10 pg/mL
Interval 2.79 to 6.03
|
6.07 pg/mL
Interval 0.0 to 7.99
|
4.04 pg/mL
Interval 2.83 to 5.76
|
8.13 pg/mL
Interval 5.53 to 11.9
|
|
Plasma Concentration at 24 Hours (C24) Post-dose Period 1
Pitavastatin lactone (metabolite)
|
22.4 pg/mL
Interval 13.9 to 36.2
|
21.7 pg/mL
Interval 13.5 to 35.0
|
12.9 pg/mL
Interval 8.01 to 20.9
|
23.2 pg/mL
Interval 14.9 to 36.2
|
32.8 pg/mL
Interval 20.3 to 52.9
|
|
Plasma Concentration at 24 Hours (C24) Post-dose Period 1
Atorvastatin
|
5.04 pg/mL
Interval 2.73 to 5.89
|
3.85 pg/mL
Interval 2.47 to 6.0
|
4.28 pg/mL
Interval 0.0 to 6.63
|
5.73 pg/mL
Interval 3.8 to 8.64
|
6.03 pg/mL
Interval 3.86 to 9.4
|
PRIMARY outcome
Timeframe: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dosePopulation: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Tmax for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
Tmax is the amount of time to reach maximum (peak) plasma drug concentration following drug administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
n=6 Participants
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=7 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1
Pitavastatin lactone (metabolite)
|
2.00 hours
Interval 1.5 to 2.0
|
2.00 hours
Interval 2.0 to 3.0
|
2.50 hours
Interval 2.0 to 6.33
|
4.00 hours
Interval 2.0 to 4.0
|
2.50 hours
Interval 2.0 to 3.0
|
|
Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1
Atorvastatin
|
0.25 hours
Interval 0.25 to 0.53
|
0.50 hours
Interval 0.5 to 6.0
|
0.25 hours
Interval 0.25 to 0.5
|
0.25 hours
Interval 0.25 to 6.0
|
0.25 hours
Interval 0.25 to 1.5
|
|
Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1
Ortho-hydroxyatorvastatin (metabolite)
|
6.00 hours
Interval 6.0 to 8.0
|
6.00 hours
Interval 3.0 to 6.0
|
5.00 hours
Interval 4.0 to 6.0
|
6.00 hours
Interval 4.0 to 8.0
|
6.00 hours
Interval 4.0 to 8.0
|
|
Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1
Rosuvastatin
|
2.00 hours
Interval 2.0 to 4.0
|
3.50 hours
Interval 0.5 to 4.0
|
3.00 hours
Interval 1.5 to 4.0
|
4.00 hours
Interval 3.0 to 4.0
|
4.00 hours
Interval 1.5 to 4.02
|
|
Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1
Midazolam
|
0.50 hours
Interval 0.5 to 1.0
|
1.00 hours
Interval 0.5 to 1.0
|
0.50 hours
Interval 0.5 to 1.0
|
0.50 hours
Interval 0.5 to 1.0
|
0.50 hours
Interval 0.5 to 1.0
|
|
Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1
Dabigatran
|
1.50 hours
Interval 1.5 to 3.0
|
1.50 hours
Interval 1.5 to 3.0
|
2.00 hours
Interval 1.0 to 4.0
|
3.00 hours
Interval 2.0 to 4.0
|
2.50 hours
Interval 2.0 to 3.0
|
|
Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1
Pitavastatin
|
0.52 hours
Interval 0.5 to 1.0
|
0.75 hours
Interval 0.5 to 1.0
|
0.50 hours
Interval 0.5 to 1.0
|
0.50 hours
Interval 0.5 to 1.5
|
1.00 hours
Interval 0.5 to 1.0
|
PRIMARY outcome
Timeframe: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dosePopulation: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of t1/2 for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
T1/2 is the elimination half-life of study drug. T1/2 is the time it takes for half of the study drug in the blood plasma to dissipate. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
n=6 Participants
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=7 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1
Midazolam
|
6.76 hours
Geometric Coefficient of Variation 30.6
|
7.99 hours
Geometric Coefficient of Variation 25.0
|
4.41 hours
Geometric Coefficient of Variation 59.6
|
7.79 hours
Geometric Coefficient of Variation 54.1
|
10.3 hours
Geometric Coefficient of Variation 33.0
|
|
Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1
Dabigatran
|
8.40 hours
Geometric Coefficient of Variation 10.7
|
6.75 hours
Geometric Coefficient of Variation 19.8
|
41.4 hours
Geometric Coefficient of Variation 47.9
|
24.0 hours
Geometric Coefficient of Variation 22.0
|
11.9 hours
Geometric Coefficient of Variation 30.3
|
|
Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1
Pitavastatin
|
19.3 hours
Geometric Coefficient of Variation 23.5
|
17.8 hours
Geometric Coefficient of Variation 26.7
|
11.8 hours
Geometric Coefficient of Variation 61.4
|
20.4 hours
Geometric Coefficient of Variation 63.6
|
22.4 hours
Geometric Coefficient of Variation 15.8
|
|
Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1
Pitavastatin lactone (metabolite)
|
20.5 hours
Geometric Coefficient of Variation 31.4
|
18.5 hours
Geometric Coefficient of Variation 15.9
|
11.0 hours
Geometric Coefficient of Variation 55.3
|
18.1 hours
Geometric Coefficient of Variation 31.0
|
22.0 hours
Geometric Coefficient of Variation 13.2
|
|
Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1
Atorvastatin
|
16.7 hours
Geometric Coefficient of Variation 14.8
|
14.9 hours
Geometric Coefficient of Variation 10.3
|
8.03 hours
Geometric Coefficient of Variation 28.5
|
17.5 hours
Geometric Coefficient of Variation 57.0
|
18.6 hours
Geometric Coefficient of Variation 41.8
|
|
Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1
Ortho-hydroxyatorvastatin (metabolite)
|
22.8 hours
Geometric Coefficient of Variation 35.7
|
21.2 hours
Geometric Coefficient of Variation 29.5
|
12.4 hours
Geometric Coefficient of Variation 25.8
|
21.9 hours
Geometric Coefficient of Variation 65.9
|
24.6 hours
Geometric Coefficient of Variation 18.3
|
|
Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1
Rosuvastatin
|
15.5 hours
Geometric Coefficient of Variation 100.2
|
16.2 hours
Geometric Coefficient of Variation 78.6
|
14.0 hours
Geometric Coefficient of Variation 107.3
|
18.8 hours
Geometric Coefficient of Variation 78.3
|
24.9 hours
Geometric Coefficient of Variation 19.4
|
PRIMARY outcome
Timeframe: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dosePopulation: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of CL/F for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
CL/F is the rate at which study drug was removed from the body. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. CL/F was to be calculated for the parent plasma analytes only, midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
n=6 Participants
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=7 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1
Midazolam
|
56.9 liters/hour
Geometric Coefficient of Variation 32.3
|
36.6 liters/hour
Geometric Coefficient of Variation 50.6
|
90.8 liters/hour
Geometric Coefficient of Variation 46.5
|
38.5 liters/hour
Geometric Coefficient of Variation 62.7
|
27.5 liters/hour
Geometric Coefficient of Variation 46.3
|
|
Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1
Dabigatran
|
175 liters/hour
Geometric Coefficient of Variation 47.3
|
178 liters/hour
Geometric Coefficient of Variation 61.5
|
52.5 liters/hour
Geometric Coefficient of Variation 74.1
|
35.7 liters/hour
Geometric Coefficient of Variation 32.3
|
61.8 liters/hour
Geometric Coefficient of Variation 70.3
|
|
Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1
Pitavastatin
|
14.5 liters/hour
Geometric Coefficient of Variation 41.1
|
19.2 liters/hour
Geometric Coefficient of Variation 52.7
|
14.8 liters/hour
Geometric Coefficient of Variation 60.0
|
15.4 liters/hour
Geometric Coefficient of Variation 58.6
|
9.84 liters/hour
Geometric Coefficient of Variation 29.7
|
|
Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1
Atorvastatin
|
304 liters/hour
Geometric Coefficient of Variation 28.7
|
343 liters/hour
Geometric Coefficient of Variation 56.9
|
304 liters/hour
Geometric Coefficient of Variation 64.7
|
210 liters/hour
Geometric Coefficient of Variation 82.9
|
196 liters/hour
Geometric Coefficient of Variation 54.0
|
|
Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1
Rosuvastatin
|
191 liters/hour
Geometric Coefficient of Variation 82.5
|
171 liters/hour
Geometric Coefficient of Variation 47.8
|
240 liters/hour
Geometric Coefficient of Variation 121.0
|
137 liters/hour
Geometric Coefficient of Variation 49.0
|
87.0 liters/hour
Geometric Coefficient of Variation 32.3
|
PRIMARY outcome
Timeframe: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dosePopulation: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Vz/F for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
Vz/F is the distribution of study drug between the plasma and the rest of the body after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. Vz/F was to be calculated for the parent plasma analytes only, midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
n=6 Participants
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=7 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1
Midazolam
|
555 liters
Geometric Coefficient of Variation 58.0
|
422 liters
Geometric Coefficient of Variation 37.5
|
579 liters
Geometric Coefficient of Variation 45.0
|
433 liters
Geometric Coefficient of Variation 16.9
|
409 liters
Geometric Coefficient of Variation 38.0
|
|
Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1
Dabigatran
|
2120 liters
Geometric Coefficient of Variation 57.9
|
1730 liters
Geometric Coefficient of Variation 46.4
|
3140 liters
Geometric Coefficient of Variation 38.4
|
1230 liters
Geometric Coefficient of Variation 36.4
|
1060 liters
Geometric Coefficient of Variation 54.1
|
|
Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1
Pitavastatin
|
405 liters
Geometric Coefficient of Variation 46.8
|
495 liters
Geometric Coefficient of Variation 46.6
|
252 liters
Geometric Coefficient of Variation 19.5
|
454 liters
Geometric Coefficient of Variation 51.9
|
317 liters
Geometric Coefficient of Variation 15.4
|
|
Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1
Atorvastatin
|
7300 liters
Geometric Coefficient of Variation 32.5
|
7380 liters
Geometric Coefficient of Variation 58.6
|
3520 liters
Geometric Coefficient of Variation 40.3
|
5310 liters
Geometric Coefficient of Variation 47.7
|
5240 liters
Geometric Coefficient of Variation 57.5
|
|
Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1
Rosuvastatin
|
4270 liters
Geometric Coefficient of Variation 117.9
|
4010 liters
Geometric Coefficient of Variation 34.4
|
4870 liters
Geometric Coefficient of Variation 63.2
|
3720 liters
Geometric Coefficient of Variation 51.3
|
3120 liters
Geometric Coefficient of Variation 35.9
|
SECONDARY outcome
Timeframe: Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dosePopulation: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-24 for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
To evaluate the effect of a single oral dose of rifampin on the AUC0-24 of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post-dose. This is a measure of the average amount of study drug in the blood plasma over a period of 24 hours after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=6 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Effect of Rifampin on AUC0-24 Post-dose Period 2
Pitavastatin lactone (metabolite)
|
1490 pg*hr/mL
Interval 1120.0 to 1970.0
|
1000 pg*hr/mL
Interval 755.0 to 1320.0
|
—
|
1070 pg*hr/mL
Interval 820.0 to 1400.0
|
1780 pg*hr/mL
Interval 1340.0 to 2350.0
|
|
Effect of Rifampin on AUC0-24 Post-dose Period 2
Atorvastatin
|
1700 pg*hr/mL
Interval 1030.0 to 2790.0
|
1760 pg*hr/mL
Interval 1180.0 to 2650.0
|
—
|
2230 pg*hr/mL
Interval 1510.0 to 3290.0
|
2420 pg*hr/mL
Interval 1610.0 to 3630.0
|
|
Effect of Rifampin on AUC0-24 Post-dose Period 2
Ortho-hydroxyatorvastatin (metabolite)
|
1720 pg*hr/mL
Interval 1030.0 to 2870.0
|
1620 pg*hr/mL
Interval 1070.0 to 2460.0
|
—
|
1580 pg*hr/mL
Interval 1060.0 to 2350.0
|
1800 pg*hr/mL
Interval 1190.0 to 2730.0
|
|
Effect of Rifampin on AUC0-24 Post-dose Period 2
Rosuvastatin
|
1010 pg*hr/mL
Interval 682.0 to 1500.0
|
842 pg*hr/mL
Interval 588.0 to 1210.0
|
—
|
1100 pg*hr/mL
Interval 779.0 to 1550.0
|
1670 pg*hr/mL
Interval 1170.0 to 2400.0
|
|
Effect of Rifampin on AUC0-24 Post-dose Period 2
Midazolam
|
186 pg*hr/mL
Interval 131.0 to 263.0
|
234 pg*hr/mL
Interval 165.0 to 332.0
|
—
|
238 pg*hr/mL
Interval 171.0 to 330.0
|
346 pg*hr/mL
Interval 224.0 to 490.0
|
|
Effect of Rifampin on AUC0-24 Post-dose Period 2
Dabigatran
|
2660 pg*hr/mL
Interval 1890.0 to 3740.0
|
3030 pg*hr/mL
Interval 2160.0 to 4260.0
|
—
|
6540 pg*hr/mL
Interval 4730.0 to 9030.0
|
5480 pg*hr/mL
Interval 3900.0 to 7700.0
|
|
Effect of Rifampin on AUC0-24 Post-dose Period 2
Pitavastatin
|
2460 pg*hr/mL
Interval 1550.0 to 3900.0
|
1860 pg*hr/mL
Interval 1170.0 to 2950.0
|
—
|
2760 pg*hr/mL
Interval 1780.0 to 4270.0
|
3360 pg*hr/mL
Interval 2120.0 to 5330.0
|
SECONDARY outcome
Timeframe: Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dosePopulation: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-last for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
To evaluate the effect of a single oral dose of rifampin on the AUC0-last of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. AUC0-last is the area under the plasma concentration-time curve from time zero to time of last measurable concentration. It is a measure of the amount of study drug in the blood plasma from pre-dose until the last measurable concentration of study drug could be determined. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=6 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Effect of Rifampin on AUC0-last Post-dose Period 2
Midazolam
|
182 pg*hr/mL
Interval 127.0 to 261.0
|
231 pg*hr/mL
Interval 161.0 to 331.0
|
—
|
236 pg*hr/mL
Interval 168.0 to 331.0
|
353 pg*hr/mL
Interval 246.0 to 505.0
|
|
Effect of Rifampin on AUC0-last Post-dose Period 2
Dabigatran
|
2830 pg*hr/mL
Interval 1950.0 to 4110.0
|
3140 pg*hr/mL
Interval 2160.0 to 4550.0
|
—
|
10400 pg*hr/mL
Interval 7310.0 to 14800.0
|
6830 pg*hr/mL
Interval 4710.0 to 9920.0
|
|
Effect of Rifampin on AUC0-last Post-dose Period 2
Pitavastatin
|
2510 pg*hr/mL
Interval 1580.0 to 4000.0
|
1890 pg*hr/mL
Interval 1190.0 to 3010.0
|
—
|
2850 pg*hr/mL
Interval 1830.0 to 4430.0
|
3480 pg*hr/mL
Interval 2180.0 to 5540.0
|
|
Effect of Rifampin on AUC0-last Post-dose Period 2
Pitavastatin lactone (metabolite)
|
1850 pg*hr/mL
Interval 1350.0 to 2520.0
|
1270 pg*hr/mL
Interval 935.0 to 1740.0
|
—
|
1470 pg*hr/mL
Interval 1100.0 to 1980.0
|
2380 pg*hr/mL
Interval 1750.0 to 3250.0
|
|
Effect of Rifampin on AUC0-last Post-dose Period 2
Atorvastatin
|
1690 pg*hr/mL
Interval 1020.0 to 2800.0
|
1760 pg*hr/mL
Interval 1160.0 to 2650.0
|
—
|
2220 pg*hr/mL
Interval 1490.0 to 3290.0
|
2420 pg*hr/mL
Interval 1600.0 to 3650.0
|
|
Effect of Rifampin on AUC0-last Post-dose Period 2
Ortho-hydroxyatorvastatin (metabolite)
|
1750 pg*hr/mL
Interval 1050.0 to 2920.0
|
1630 pg*hr/mL
Interval 1070.0 to 2470.0
|
—
|
1610 pg*hr/mL
Interval 1080.0 to 2400.0
|
1850 pg*hr/mL
Interval 1220.0 to 2820.0
|
|
Effect of Rifampin on AUC0-last Post-dose Period 2
Rosuvastatin
|
1040 pg*hr/mL
Interval 698.0 to 1560.0
|
854 pg*hr/mL
Interval 592.0 to 1230.0
|
—
|
1150 pg*hr/mL
Interval 806.0 to 1630.0
|
1740 pg*hr/mL
Interval 1200.0 to 2500.0
|
SECONDARY outcome
Timeframe: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dosePopulation: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Cmax for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
To evaluate the effect of a single oral dose of rifampin on the Cmax of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. Cmax is the peak plasma concentration of study drug after administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=6 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Effect of Rifampin on Cmax Post-dose Period 2
Midazolam
|
73.0 pg/mL
Interval 54.5 to 97.9
|
81.4 pg/mL
Interval 60.7 to 109.0
|
—
|
75.4 pg/mL
Interval 57.1 to 99.7
|
92.5 pg/mL
Interval 69.0 to 124.0
|
|
Effect of Rifampin on Cmax Post-dose Period 2
Dabigatran
|
243 pg/mL
Interval 173.0 to 342.0
|
351 pg/mL
Interval 249.0 to 494.0
|
—
|
422 pg/mL
Interval 305.0 to 584.0
|
443 pg/mL
Interval 314.0 to 624.0
|
|
Effect of Rifampin on Cmax Post-dose Period 2
Pitavastatin
|
819 pg/mL
Interval 485.0 to 1380.0
|
599 pg/mL
Interval 354.0 to 1010.0
|
—
|
981 pg/mL
Interval 591.0 to 1630.0
|
860 pg/mL
Interval 509.0 to 1450.0
|
|
Effect of Rifampin on Cmax Post-dose Period 2
Pitavastatin lactone (metabolite)
|
131 pg/mL
Interval 108.0 to 161.0
|
102 pg/mL
Interval 83.7 to 125.0
|
—
|
88.4 pg/mL
Interval 72.8 to 107.0
|
119 pg/mL
Interval 97.3 to 145.0
|
|
Effect of Rifampin on Cmax Post-dose Period 2
Atorvastatin
|
505 pg/mL
Interval 305.0 to 835.0
|
405 pg/mL
Interval 269.0 to 611.0
|
—
|
531 pg/mL
Interval 354.0 to 796.0
|
508 pg/mL
Interval 337.0 to 766.0
|
|
Effect of Rifampin on Cmax Post-dose Period 2
Ortho-hydroxyatorvastatin (metabolite)
|
215 pg/mL
Interval 124.0 to 372.0
|
198 pg/mL
Interval 126.0 to 310.0
|
—
|
150 pg/mL
Interval 97.1 to 231.0
|
174 pg/mL
Interval 111.0 to 272.0
|
|
Effect of Rifampin on Cmax Post-dose Period 2
Rosuvastatin
|
254 pg/mL
Interval 152.0 to 425.0
|
236 pg/mL
Interval 148.0 to 376.0
|
—
|
208 pg/mL
Interval 133.0 to 327.0
|
396 pg/mL
Interval 248.0 to 633.0
|
SECONDARY outcome
Timeframe: 24 hours post-dosePopulation: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of C24 for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
To evaluate the effect of a single oral dose of rifampin on the C24 of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. C24 is a measure of the plasma study drug concentration 24 hours post-dose. C24 is reported as median (minimum and maximum) in severe renal impairment arm due to zero values. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=6 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Effect of Rifampin on C24 Post-dose Period 2
Midazolam
|
0.00 pg/mL
Interval 0.0 to 0.921
|
0.601 pg/mL
Interval 0.0 to 1.33
|
—
|
0.394 pg/mL
Interval 0.0 to 4.15
|
1.42 pg/mL
Interval 0.701 to 2.89
|
|
Effect of Rifampin on C24 Post-dose Period 2
Dabigatran
|
31.1 pg/mL
Interval 20.2 to 47.9
|
27.5 pg/mL
Interval 17.9 to 42.4
|
—
|
174 pg/mL
Interval 115.0 to 263.0
|
100 pg/mL
Interval 65.1 to 154.0
|
|
Effect of Rifampin on C24 Post-dose Period 2
Pitavastatin
|
4.70 pg/mL
Interval 2.49 to 8.87
|
4.72 pg/mL
Interval 2.5 to 8.91
|
—
|
7.01 pg/mL
Interval 3.81 to 12.9
|
10.5 pg/mL
Interval 5.54 to 19.8
|
|
Effect of Rifampin on C24 Post-dose Period 2
Pitavastatin lactone (metabolite)
|
20.7 pg/mL
Interval 14.3 to 30.0
|
17.1 pg/mL
Interval 11.8 to 24.8
|
—
|
21.3 pg/mL
Interval 15.0 to 30.3
|
34.0 pg/mL
Interval 23.5 to 49.3
|
|
Effect of Rifampin on C24 Post-dose Period 2
Atorvastatin
|
1.76 pg/mL
Interval 0.0 to 2.32
|
1.35 pg/mL
Interval 0.0 to 3.2
|
—
|
2.98 pg/mL
Interval 0.0 to 16.1
|
2.98 pg/mL
Interval 1.65 to 5.4
|
|
Effect of Rifampin on C24 Post-dose Period 2
Ortho-hydroxyatorvastatin (metabolite)
|
6.28 pg/mL
Interval 2.71 to 14.5
|
5.57 pg/mL
Interval 2.81 to 11.1
|
—
|
7.23 pg/mL
Interval 3.7 to 14.1
|
9.96 pg/mL
Interval 5.02 to 19.8
|
|
Effect of Rifampin on C24 Post-dose Period 2
Rosuvastatin
|
4.18 pg/mL
Interval 1.22 to 9.99
|
2.42 pg/mL
Interval 0.0 to 6.92
|
—
|
4.47 pg/mL
Interval 2.34 to 8.53
|
6.97 pg/mL
Interval 3.53 to 13.8
|
SECONDARY outcome
Timeframe: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dosePopulation: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Tmax for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
To evaluate the effect of a single oral dose of rifampin on the Tmax of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. Tmax is the amount of time to reach maximum (peak) plasma drug concentration following drug administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=6 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Effect of Rifampin on Tmax Post-dose Period 2
Midazolam
|
0.50 hours
Interval 0.5 to 1.0
|
1.00 hours
Interval 0.5 to 1.0
|
—
|
0.50 hours
Interval 0.5 to 1.0
|
0.75 hours
Interval 0.5 to 1.0
|
|
Effect of Rifampin on Tmax Post-dose Period 2
Dabigatran
|
2.50 hours
Interval 2.0 to 4.0
|
2.50 hours
Interval 1.5 to 3.0
|
—
|
3.50 hours
Interval 2.0 to 4.05
|
3.00 hours
Interval 2.0 to 4.0
|
|
Effect of Rifampin on Tmax Post-dose Period 2
Pitavastatin
|
1.00 hours
Interval 0.5 to 3.0
|
1.00 hours
Interval 1.0 to 2.0
|
—
|
1.00 hours
Interval 0.5 to 1.0
|
1.00 hours
Interval 0.5 to 2.0
|
|
Effect of Rifampin on Tmax Post-dose Period 2
Pitavastatin lactone (metabolite)
|
3.00 hours
Interval 1.5 to 4.0
|
2.00 hours
Interval 1.5 to 4.05
|
—
|
3.00 hours
Interval 1.5 to 4.0
|
4.00 hours
Interval 2.0 to 12.0
|
|
Effect of Rifampin on Tmax Post-dose Period 2
Atorvastatin
|
1.00 hours
Interval 1.0 to 1.5
|
1.50 hours
Interval 1.0 to 2.0
|
—
|
0.50 hours
Interval 0.5 to 1.0
|
1.50 hours
Interval 0.5 to 2.0
|
|
Effect of Rifampin on Tmax Post-dose Period 2
Ortho-hydroxyatorvastatin (metabolite)
|
1.75 hours
Interval 1.0 to 4.0
|
3.00 hours
Interval 1.0 to 4.05
|
—
|
1.75 hours
Interval 1.0 to 4.05
|
2.50 hours
Interval 1.5 to 4.0
|
|
Effect of Rifampin on Tmax Post-dose Period 2
Rosuvastatin
|
1.00 hours
Interval 1.0 to 3.0
|
2.00 hours
Interval 1.0 to 6.0
|
—
|
1.00 hours
Interval 1.0 to 2.0
|
2.00 hours
Interval 1.0 to 3.0
|
SECONDARY outcome
Timeframe: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dosePopulation: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of t1/2 for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
To evaluate the effect of a single oral dose of rifampin on the t1/2 of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. T1/2 is the elimination half-life of study drug. T1/2 is the time it takes for half of the study drug in the blood plasma to dissipate. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=6 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Effect of Rifampin on t1/2 Post-dose Period 2
Midazolam
|
4.12 hours
Geometric Coefficient of Variation 26.7
|
4.97 hours
Geometric Coefficient of Variation 22.0
|
—
|
4.14 hours
Geometric Coefficient of Variation 19.5
|
5.49 hours
Geometric Coefficient of Variation 26.2
|
|
Effect of Rifampin on t1/2 Post-dose Period 2
Dabigatran
|
7.57 hours
Geometric Coefficient of Variation 19.0
|
6.48 hours
Geometric Coefficient of Variation 13.7
|
—
|
19.4 hours
Geometric Coefficient of Variation 21.3
|
11.3 hours
Geometric Coefficient of Variation 33.1
|
|
Effect of Rifampin on t1/2 Post-dose Period 2
Pitavastatin
|
8.40 hours
Geometric Coefficient of Variation 75.8
|
6.50 hours
Geometric Coefficient of Variation 30.3
|
—
|
6.99 hours
Geometric Coefficient of Variation 62.8
|
11.5 hours
Geometric Coefficient of Variation 71.6
|
|
Effect of Rifampin on t1/2 Post-dose Period 2
Pitavastatin lactone (metabolite)
|
21.0 hours
Geometric Coefficient of Variation 22.5
|
16.5 hours
Geometric Coefficient of Variation 33.9
|
—
|
17.2 hours
Geometric Coefficient of Variation 41.0
|
17.7 hours
Geometric Coefficient of Variation 25.2
|
|
Effect of Rifampin on t1/2 Post-dose Period 2
Atorvastatin
|
3.22 hours
Geometric Coefficient of Variation 8.6
|
2.76 hours
Geometric Coefficient of Variation 8.4
|
—
|
3.14 hours
Geometric Coefficient of Variation 18.9
|
2.99 hours
Geometric Coefficient of Variation 21.1
|
|
Effect of Rifampin on t1/2 Post-dose Period 2
Ortho-hydroxyatorvastatin (metabolite)
|
3.83 hours
Geometric Coefficient of Variation 19.7
|
3.49 hours
Geometric Coefficient of Variation 11.7
|
—
|
4.56 hours
Geometric Coefficient of Variation 43.7
|
4.25 hours
Geometric Coefficient of Variation 39.7
|
|
Effect of Rifampin on t1/2 Post-dose Period 2
Rosuvastatin
|
9.64 hours
Geometric Coefficient of Variation 83.8
|
6.76 hours
Geometric Coefficient of Variation 94.3
|
—
|
4.89 hours
Geometric Coefficient of Variation 49.9
|
7.48 hours
Geometric Coefficient of Variation 19.8
|
SECONDARY outcome
Timeframe: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dosePopulation: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of CL/F for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
To evaluate the effect of a single oral dose of rifampin on the CL/F of midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvatatin. CL/F is the rate at which study drug was removed from the body. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=6 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Effect of Rifampin on CL/F Post-dose Period 2
Midazolam
|
53.0 liters/hour
Geometric Coefficient of Variation 34.8
|
41.8 liters/hour
Geometric Coefficient of Variation 28.4
|
—
|
40.5 liters/hour
Geometric Coefficient of Variation 57.7
|
27.8 liters/hour
Geometric Coefficient of Variation 52.0
|
|
Effect of Rifampin on CL/F Post-dose Period 2
Dabigatran
|
92.8 liters/hour
Geometric Coefficient of Variation 41.5
|
85.6 liters/hour
Geometric Coefficient of Variation 40.0
|
—
|
26.3 liters/hour
Geometric Coefficient of Variation 41.6
|
38.9 liters/hour
Geometric Coefficient of Variation 58.7
|
|
Effect of Rifampin on CL/F Post-dose Period 2
Pitavastatin
|
3.95 liters/hour
Geometric Coefficient of Variation 51.8
|
5.24 liters/hour
Geometric Coefficient of Variation 75.8
|
—
|
3.57 liters/hour
Geometric Coefficient of Variation 50.0
|
2.86 liters/hour
Geometric Coefficient of Variation 60.4
|
|
Effect of Rifampin on CL/F Post-dose Period 2
Atorvastatin
|
58.6 liters/hour
Geometric Coefficient of Variation 49.4
|
56.4 liters/hour
Geometric Coefficient of Variation 62.2
|
—
|
44.2 liters/hour
Geometric Coefficient of Variation 57.6
|
41.1 liters/hour
Geometric Coefficient of Variation 30.3
|
|
Effect of Rifampin on CL/F Post-dose Period 2
Rosuvastatin
|
47.1 liters/hour
Geometric Coefficient of Variation 51.1
|
57.9 liters/hour
Geometric Coefficient of Variation 63.3
|
—
|
38.6 liters/hour
Geometric Coefficient of Variation 37.7
|
28.9 liters/hour
Geometric Coefficient of Variation 41.1
|
SECONDARY outcome
Timeframe: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dosePopulation: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Vz/F for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
To evaluate the effect of a single oral dose of rifampin on the Vz/F of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. Vz/F is the distribution of study drug between the plasma and the rest of the body after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Outcome measures
| Measure |
Mild Impairment
n=6 Participants
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control
n=6 Participants
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
End-Stage Renal Disease
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings
|
Severe Impairment
n=6 Participants
Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment
n=6 Participants
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|
|
Effect of Rifampin on Vz/F Post-dose Period 2
Midazolam
|
315 liters
Geometric Coefficient of Variation 30.8
|
300 liters
Geometric Coefficient of Variation 36.3
|
—
|
242 liters
Geometric Coefficient of Variation 44.6
|
220 liters
Geometric Coefficient of Variation 56.5
|
|
Effect of Rifampin on Vz/F Post-dose Period 2
Dabigatran
|
1010 liters
Geometric Coefficient of Variation 45.2
|
800 liters
Geometric Coefficient of Variation 41.1
|
—
|
733 liters
Geometric Coefficient of Variation 29.2
|
632 liters
Geometric Coefficient of Variation 36.3
|
|
Effect of Rifampin on Vz/F Post-dose Period 2
Pitavastatin
|
47.8 liters
Geometric Coefficient of Variation 82.5
|
49.2 liters
Geometric Coefficient of Variation 72.1
|
—
|
36.0 liters
Geometric Coefficient of Variation 38.7
|
47.3 liters
Geometric Coefficient of Variation 85.8
|
|
Effect of Rifampin on Vz/F Post-dose Period 2
Atorvastatin
|
272 liters
Geometric Coefficient of Variation 58.4
|
225 liters
Geometric Coefficient of Variation 68.7
|
—
|
200 liters
Geometric Coefficient of Variation 55.4
|
177 liters
Geometric Coefficient of Variation 38.2
|
|
Effect of Rifampin on Vz/F Post-dose Period 2
Rosuvastatin
|
654 liters
Geometric Coefficient of Variation 40.8
|
565 liters
Geometric Coefficient of Variation 76.1
|
—
|
272 liters
Geometric Coefficient of Variation 39.7
|
313 liters
Geometric Coefficient of Variation 58.2
|
Adverse Events
End Stage Renal Disease: Microdose Cocktail Alone
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Severe Impairment: Microdose Cocktail Alone
Serious events: 1 serious events
Other events: 2 other events
Deaths: 0 deaths
Severe Impairment: Microdose Cocktail + Rifampin
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Moderate Impairment: Microdose Cocktail Alone
Serious events: 0 serious events
Other events: 2 other events
Deaths: 0 deaths
Moderate Impairment: Microdose Cocktail + Rifampin
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Mild Impairment: Microdose Cocktail Alone
Serious events: 0 serious events
Other events: 3 other events
Deaths: 0 deaths
Mild Impairment: Microdose Cocktail + Rifampin
Serious events: 0 serious events
Other events: 2 other events
Deaths: 0 deaths
Healthy Control: Microdose Cocktail Alone
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Healthy Control: Microdose Cocktail + Rifampin
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
End Stage Renal Disease: Microdose Cocktail Alone
n=6 participants at risk
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution).
Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings.
|
Severe Impairment: Microdose Cocktail Alone
n=7 participants at risk
Participants with \<30 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution).
|
Severe Impairment: Microdose Cocktail + Rifampin
n=6 participants at risk
Participants with \<30 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment: Microdose Cocktail Alone
n=6 participants at risk
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution).
|
Moderate Impairment: Microdose Cocktail + Rifampin
n=6 participants at risk
Moderate ImpairmentEdit Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Mild Impairment: Microdose Cocktail Alone
n=7 participants at risk
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution).
|
Mild Impairment: Microdose Cocktail + Rifampin
n=6 participants at risk
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control: Microdose Cocktail Alone
n=6 participants at risk
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control: Microdose Cocktail + Rifampin
n=6 participants at risk
Participants with ≥90 mL/min creatinine clearance. Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|---|---|---|---|
|
Cardiac disorders
Cardiac failure congestive
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
14.3%
1/7 • Number of events 1 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/7 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
|
Renal and urinary disorders
Acute kidney injury
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
14.3%
1/7 • Number of events 1 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/7 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
Other adverse events
| Measure |
End Stage Renal Disease: Microdose Cocktail Alone
n=6 participants at risk
Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution).
Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings.
|
Severe Impairment: Microdose Cocktail Alone
n=7 participants at risk
Participants with \<30 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution).
|
Severe Impairment: Microdose Cocktail + Rifampin
n=6 participants at risk
Participants with \<30 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Moderate Impairment: Microdose Cocktail Alone
n=6 participants at risk
Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution).
|
Moderate Impairment: Microdose Cocktail + Rifampin
n=6 participants at risk
Moderate ImpairmentEdit Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Mild Impairment: Microdose Cocktail Alone
n=7 participants at risk
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution).
|
Mild Impairment: Microdose Cocktail + Rifampin
n=6 participants at risk
Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control: Microdose Cocktail Alone
n=6 participants at risk
Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
Healthy Control: Microdose Cocktail + Rifampin
n=6 participants at risk
Participants with ≥90 mL/min creatinine clearance. Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.
|
|---|---|---|---|---|---|---|---|---|---|
|
Gastrointestinal disorders
Diarrhoea
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/7 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
16.7%
1/6 • Number of events 1 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/7 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
|
General disorders
Fatigue
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/7 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/7 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
16.7%
1/6 • Number of events 1 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
|
Investigations
Blood potassium decreased
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/7 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
14.3%
1/7 • Number of events 1 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
|
Nervous system disorders
Headache
|
16.7%
1/6 • Number of events 1 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/7 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
16.7%
1/6 • Number of events 1 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/7 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
16.7%
1/6 • Number of events 1 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
|
Nervous system disorders
Somnolence
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
28.6%
2/7 • Number of events 2 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
33.3%
2/6 • Number of events 2 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
28.6%
2/7 • Number of events 2 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
0.00%
0/6 • Up tp approximately 30 days (including 14 days following the last dose)
All participants who received any dose are included. Adverse events were summarized by renal function group assignment and dose received (microdose cocktail alone or microdose cocktail + rifampin).
|
Additional Information
Senior Vice President, Global Clinical Development
Merck Sharp & Dohme Corp.
Phone: 1-800-672-6372
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee The Sponsor will provide separate guidance on the criteria for publication of clinical trial data when contacted for permission to publish.
- Publication restrictions are in place
Restriction type: OTHER