Trial Outcomes & Findings for A Study To Investigate The Pharmacokinetics, Safety And Tolerability Of An Intravenous And Oral Form Of A Compound In Subjects With Varying Degrees Of Renal Impairment And Normal Renal Function (NCT NCT00759564)

This was a fixed sequence design study (not a complete 2 way crossover) in parallel groups of participants with varying degrees of renal impairment, where all subjects received the intravenous formulation in first period and then received the oral formulation in second period.

Participants were planned to receive CP-70,429 800 milligram (mg) in all reporting groups. For severe renal impairment group, CP-70,429 dose was decreased from 800 mg to 200 mg as per protocol amendment. Only 1 participant received 800 mg dose and was excluded from all descriptive and statistical analyses as per change in planned analysis.

A Study To Investigate The Pharmacokinetics, Safety And Tolerability Of An Intravenous And Oral Form Of A Compound In Subjects With Varying Degrees Of Renal Impairment And Normal Renal Function

PF-03709270 is an oral prodrug of CP-70,429. Upon oral absorption, PF-03709270 is rapidly hydrolyzed, yielding the active drug CP-70,429. Cmax of CP-70429 following CP-70,429 intravenous dose was reported.

Area under the plasma concentration time-curve from zero (pre-dose) to the time of last measured concentration (AUClast).

AUC (0-inf) is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).

Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau).

PF-03709270 is an oral prodrug of CP-70,429. Upon oral absorption, PF-03709270 is rapidly hydrolyzed, yielding the active drug CP-70,429. Cmax of CP-70429 following CP-70,429 intravenous dose was reported.

Area under the plasma concentration time-curve from zero (pre-dose) to the time of last measured concentration (AUClast).

AUC (0-inf) is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).

Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau).

Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.

Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing given intravenous dose by AUC inf. AUC inf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. It was calculated by dividing the given oral dose by AUCinf. AUC inf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).

Duration was calculated by subtracting the time at which the plasma concentrations exceeded 0.5 microgram per milliliter (mcg/mL) at the ascending part of the concentration-time profile from the time at which the plasma concentrations fell below 0.5 mcg/mL at the descending part of the profile. If these times fell between 2 observed concentrations, a method of linear interpolation was used for best estimation.

Duration was calculated by subtracting the time at which the plasma concentrations exceeded 0.5 mcg/mL at the ascending part of the concentration-time profile from the time at which the plasma concentrations fell below 0.5 mcg/mL at the descending part of the profile. If these times fell between 2 observed concentrations, a method of linear interpolation was used for best estimation.

Duration was calculated by subtracting the time at which the plasma concentrations exceeded 1.0 mcg/mL at the ascending part of the concentration-time profile from the time at which the plasma concentrations fell below 1.0 mcg/mL at the descending part of the profile. If these times fell between 2 observed concentrations, a method of linear interpolation was used for best estimation.

Duration was calculated by subtracting the time at which the plasma concentrations exceeded 0.5 mcg/mL at the ascending part of the concentration-time profile from the time at which the plasma concentrations fell below 0.5 mcg/mL at the descending part of the profile. If these times fell between 2 observed concentrations, a method of linear interpolation was used for best estimation.

PF-03709270 is an oral prodrug of CP-70,429. Upon oral absorption, PF-03709270 is rapidly hydrolyzed, yielding the active drug CP-70,429 and metabolites.

Concentration versus time summary was calculated by setting concentration values below the lower limit of quantification (LLQ =100 ng/mL) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) =0.

Concentration versus time summary was calculated by setting concentration values below the lower limit of quantification (LLQ =100 ng/mL) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) =0.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 7-10 days after last dose that were absent before treatment or that worsened relative to pre-treatment state.

Criteria for laboratory test abnormality: Hematology (hemoglobin, hematocrit, red blood corpuscles \[RBC\] count: less than \[\<\]0.8\*lower limit of normal \[LLN\], platelets: \<0.5\*LLN/greater than \[\>\]1.75\*upper limit of normal \[ULN\], leukocytes: \<0.6\*LLN or \>1.5\*ULN, lymphocytes, total neutrophils: \<0.8\*LLN or \>1.2\*ULN, basophils, eosinophil, monocytes: \>1.2\*ULN); Liver Function (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase: \>0.3\*ULN, total protein, albumin: \<0.8\*LLN or \>1.2\*ULN); total bilirubin, direct bilirubin, indirect bilirubin: \>1.5\*ULN; Renal Function (blood urea nitrogen, creatinine: \>1.3\*ULN, uric acid: \>1.2\*ULN); Electrolytes (sodium: \<0.95\*LLN or \>1.05\*ULN, potassium, chloride, calcium, bicarbonate: \<0.9\*LLN or \>1.1\*ULN; creatine kinase: \>2.0\*ULN; glucose fasting: \<0.6\*LLN or \>1.5\*ULN, urine white blood corpuscles \[WBC\] and RBC: greater than or equal to (\>=) 6/High Power Field \[HPF\]).

Criteria for vital signs abnormalities included supine/sitting pulse rate of \<40 beats per minute (bpm) or \>120 bpm, supine systolic blood pressure (SBP) of \<90 millimeter of mercury (mmHg), \>=30 mmHg maximum increase and decrease from baseline in same posture, supine diastolic blood pressure (DBP) of \<50 mmHg, \>=20 mmHg maximum increase and decrease from baseline in same posture, heart rate \<=45 beats per minute (bpm) or \>=120 bpm or decrease/increase of \>=15 bpm.

Criteria for abnormal ECG (12-lead) values were defined as: maximum PR interval \>=300 millisecond (msec) and maximum increase of \>=25 percent for baseline value of \>200 msec and \>=50% for baseline value of \<=200 msec for PR interval, QRS interval \>=200 msec; QT interval corrected using the Fridericia formula (QTcF) \>=500 msec or increase of \>45 msec.

Physical examination included examination of the skin, eyes, ears, throat, neck, and cardiac, respiratory, gastrointestinal and musculoskeletal systems. The examination assessed the participants for any potential changes in physical status, as determined by the investigator. Any untoward findings identified on physical exams conducted after the administration of the first dose of study medication was captured as an adverse event.