Trial Outcomes & Findings for STUDY OF PF-07321332 IN HEALTHY PARTICIPANTS (NCT NCT04756531)

This was a 5-part study combining PART-1: single ascending dose (SAD), PART-2: multiple ascending dose (MAD), PART-3: relative bioavailability/food effect (rBA/FE), PART-4: metabolism and excretion (M\&E) and PART-5: supratherapeutic exposure (SE).

STUDY OF PF-07321332 IN HEALTHY PARTICIPANTS

An Adverse Event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of study intervention and up to 36 days after last dose of study intervention. A serious adverse event (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. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator.

Vital signs (temperature, respiratory rate, pulse rate \[PR\], systolic blood pressure \[SBP\], and diastolic blood pressure \[DBP\]) were obtained with participants following at least 5 minutes of supine rest. Categorical criteria were defined as DBP: value \<50 millimeters of mercury (mm Hg), increase \>=20 mm Hg, or decrease \>=20 mm Hg; PR: value \<40 beats per minute (bpm) or value \>120 bpm; SBP: value \<90 mm Hg, increase \>=30 mm Hg, or decrease \>=30 mm Hg. Clinical significance of vital signs was determined at the investigator's discretion. The analysis population included all participants who received at least 1 dose of study intervention and had at least 1 assessment undertaken post treatment.

Laboratory parameters included hematology, chemistry, urinalysis, and other (urine drug screening, Severe Acute Respiratory Syndrome Coronavirus 2 \[SARS-CoV-2\] reverse transcription polymerase chain reaction \[RT-PCR\], estimated glomerular filtration rate \[eGFR\], pregnancy test \[beta human chorionic gonadotropin \[b-hCG\]\], activated partial thromboplastin time \[aPTT\], prothrombin time \[PT\] - international normalized ratio \[INR\], fibrinogen, thyroid stimulating hormone \[TSH\], Free thyroxine \[T4\]). The clinical significance of laboratory parameters was determined at the investigator's discretion. The analysis population included all participants who received at least 1 dose of the study intervention.

An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of study intervention and up to 36 days after last dose of study intervention. 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. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator.

Vital signs (temperature, respiratory rate, PR, SBP, DBP) were obtained with participants following at least 5 minutes of supine rest. Categorical criteria were defined as DBP: value \<50 mm Hg, increase \>=20 mm Hg, or decrease \>=20 mm Hg; PR: value \<40 bpm or value \>120 bpm; SBP: value \<90 mm Hg, increase \>=30 mm Hg, or decrease \>=30 mm Hg. Clinical significance of vital signs was determined at the investigator's discretion.

Laboratory parameters included hematology, chemistry, urinalysis, and other (urine drug screening, SARS-CoV-2 RT-PCR, eGFR, pregnancy test \[b-hCG\], aPTT, PT-INR, fibrinogen, TSH, Free T4). The clinical significance of laboratory parameters was determined at the investigator's discretion. The analysis population included all participants who received at least 1 dose of the study intervention.

AUClast is area under the concentration-time profile from time 0 (pre-dose) to the time of the last quantifiable concentration.

AUCinf is area under the concentration-time profile from time 0 (pre-dose) extrapolated to infinite time. Natural log transformed AUCinf for PF-07321332 was analyzed to provide an estimate of the ratio of adjusted geometric means (Test \[tablet\] /Reference \[suspension\]) and 90% CI for the ratio.

Cmax is maximum plasma concentration. It was observed directly from data. Natural log transformed Cmax for PF-07321332 was analyzed to provide an estimate of the ratio of adjusted geometric means (Test \[tablet\] /Reference \[suspension\]) and 90% CI for the ratio.

Total recovery of drug-related material excreted in urine, expressed as a percent of total dose administered, measured by fluorine-19 nuclear magnetic resonance (19F-NMR).

Total recovery of drug-related material excreted in feces, expressed as a percent of total dose administered, measured by 19F-NMR.

Total recovery of drug-related material excreted in urine and feces combined, expressed as a percent of total dose administered, measured by 19F-NMR.

An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of study intervention and up to 36 days after last dose of study intervention. 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. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator.

Vital signs (temperature, respiratory rate, PR, SBP, DBP) were obtained with participants following at least 5 minutes of supine rest. Categorical criteria were defined as DBP: value \<50 mm Hg, increase \>=20 mm Hg, or decrease \>=20 mm Hg; PR: value \<40 bpm or value \>120 bpm; SBP: value \<90 mm Hg, increase \>=30 mm Hg, or decrease \>=30 mm Hg. Clinical significance of vital signs was determined at the investigator's discretion.

Laboratory parameters included hematology, chemistry, urinalysis, and other (urine drug screening, SARS-CoV-2 RT-PCR, eGFR, pregnancy test \[b-hCG\], aPTT, PT-INR, fibrinogen, TSH, Free T4). The clinical significance of laboratory parameters was determined at the investigator's discretion. The analysis population included all participants who received at least 1 dose of the study intervention.

Cmax is maximum plasma concentration. It was observed directly from data.

Time to reach Cmax.

AUClast is area under the concentration-time profile from time 0 (pre-dose) to the time of the last quantifiable concentration.

AUCinf is area under the concentration-time profile from time 0 (pre-dose) extrapolated to infinite time.

Cmax is maximum plasma concentration. It was observed directly from data. Cmax(dn) = Cmax / dose.

AUCinf is area under the concentration-time profile from time 0 (pre-dose) extrapolated to infinite time. AUCinf(dn) = AUCinf/dose.

AUClast is area under the concentration-time profile from time 0 (pre-dose) to the time of the last quantifiable concentration. AUClast(dn) = AUClast /dose.

Vz/F = Dose/(AUCinf\*kel), where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

CL/F is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F = Dose/AUCinf.

t1/2 is the time measured for the plasma concentration of drug to decrease by one half of its initial concentration.

Cmax is maximum plasma concentration. It was observed directly from data.

Time to reach Cmax.

AUCtau is area under the concentration-time profile from time 0 (pre-dose) to end of dosing interval, where dosing interval was 12 hours.

Cmax is maximum plasma concentration. It was observed directly from data. Cmax(dn) = Cmax / dose.

AUCtau is area under the concentration-time profile from time 0 (pre-dose) to end of dosing interval, where dosing interval was 12 hours. AUCtau(dn) = AUCtau/dose.

Cav is average plasma concentration over the dosing interval, where dosing interval was 12 hours.

Cmin is minimum observed concentration during the dosing interval, where dosing interval was 12 hours.

Rac was calculated as Day 5 or Day 10 AUCtau/Day 1 AUCtau.

Rac,Cmax is Day 5 or Day 10 Cmax/Day 1 Cmax.

PTR is defined as peak-to-trough ratio. PTR = Cmax/Cmin.

CL/F is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F = Dose/AUCtau.

Vz/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F = Dose/(AUCinf\*kel), where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

t1/2 is the time measured for the plasma concentration of drug to decrease by one-half of its initial concentration.

Ae is the cumulative amount of drug recovered unchanged in urine during the dosing interval, where the dosing interval is 12 hours. Aetau is the sum of (urine volume × urine concentration) for each collection over the dosing interval.

Aetau% is defined as percent of dose excreted in urine as unchanged drug over the dosing interval, where the dosing interval is 12 hours. Aetau% = Aetau / Dose \* 100.

CLr is defined as the renal clearance. CLr = Aetau / AUCtau, where the dosing interval was 12 hours.

AUClast is area under the concentration-time profile from time 0 (pre-dose) to the time of the last quantifiable concentration. Natural log transformed AUClast for PF-07321332 was analyzed to provide an estimate of the ratio of adjusted geometric means (Test \[tablet under fed condition\] /Reference \[tablet under fasted condition\]) and 90% CI for the ratio.

AUCinf is area under the concentration-time profile from time 0 (pre-dose) extrapolated to infinite time. Natural log transformed AUCinf for PF-07321332 was analyzed to provide an estimate of the ratio of adjusted geometric means (Test \[tablet under fed condition\] /Reference \[tablet under fasted condition\]) and 90% CI for the ratio.

Cmax is maximum plasma concentration. It was observed directly from data. Natural log transformed Cmax for PF-07321332 was analyzed to provide an estimate of the ratio of adjusted geometric means (Test \[tablet under fed condition\] /Reference \[tablet under fasted condition\]) and 90% CI for the ratio.

Cmax is maximum plasma concentration. It was observed directly from data. Cmax(dn) = Cmax / dose.

Time to reach Cmax.

AUClast is area under the concentration-time profile from time 0 (pre-dose) to the time of the last quantifiable concentration. AUClast(dn) = AUClast /dose.

AUCinf is area under the concentration-time profile from time 0 (pre-dose) extrapolated to infinite time. AUCinf(dn) = AUCinf/dose.

CL/F is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F = Dose/AUCinf.

Vz/F = Dose/(AUCinf\*kel), where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

t1/2 is the time measured for the plasma concentration of drug to decrease by one-half of its initial concentration.

An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of study intervention and up to 36 days after last dose of study intervention. 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. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator.

Laboratory parameters included hematology, chemistry, urinalysis, and other (urine drug screening, SARS-CoV-2 RT-PCR, eGFR, pregnancy test \[b-hCG\], aPTT, PT-INR, fibrinogen, TSH, Free T4). The clinical significance of laboratory parameters was determined at the investigator's discretion. The analysis population included all participants who received at least 1 dose of the study intervention.

Cmax is maximum plasma concentration. It was observed directly from data.

Tmax is time to reach Cmax.

AUClast is area under the concentration-time profile from time 0 (pre-dose) to the time of the last quantifiable concentration.

AUCinf is area under the concentration-time profile from time 0 (pre-dose) extrapolated to infinite time.

CL/F is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F = Dose/AUCinf.

Vz/F = Dose/(AUCinf\*kel), where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

t1/2 is the time measured for the plasma concentration of drug to decrease by one-half of its initial concentration.

An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of study intervention and up to 36 days after last dose of study intervention. 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. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator.

Laboratory parameters included hematology, chemistry, urinalysis, and other (urine drug screening, SARS-CoV-2 RT-PCR, eGFR, pregnancy test \[b-hCG\], aPTT, PT-INR, fibrinogen, TSH, Free T4). The clinical significance of laboratory parameters was determined at the investigator's discretion.

Cmax is maximum plasma concentration. It was observed directly from data.

Time to reach Cmax.

AUClast is area under the concentration-time profile from time 0 (pre-dose) to the time of the last quantifiable concentration.

AUCinf is area under the concentration-time profile from time 0 (pre-dose) extrapolated to infinite time.

t1/2 is the time measured for the plasma concentration of drug to decrease by one-half of its initial concentration.