A Study To Evaluate The Pharmacokinetics, Excretion, Mass Balance and Metabolism of PF-07265803

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the pharmacokinetics, excretion, mass balance and metabolism of PF-07265803 (formerly known as ARRY-371797) in approximately 6 healthy adult male participants.

Official Title
-----------------
A PHASE 1, OPEN-LABEL, SINGLE-PERIOD, NON-RANDOMIZED STUDY TO EVALUATE THE PHARMACOKINETICS, EXCRETION, MASS BALANCE AND METABOLISM OF [14C]PF-07265803 ADMINISTERED ORALLY TO HEALTHY ADULT MALE PARTICIPANTS

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: PF-07265803


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must be male and ≥18 years of age at the time of signing the informed consent. Male participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and electrocardiogram (ECG) monitoring. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests , lifestyle considerations , and other study procedures. Body Mass Index of 18.0 to 32 kg/m2; and a total body weight >50 kg (110 lb). Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy, gastric bypass, duodenotomy, colectomy, history of inflammatory bowel disease). History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, or HCVAb. Hepatitis B vaccination is allowed. Participants with a history of irregular bowel movements; e.g., less than 1 bowel movement per day, regular episodes of diarrhea or constipation, irritable bowel syndrome (IBS) or lactose intolerance. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality or other conditions or situations related to COVID-19 pandemic (eg. Contact with positive case)] that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half lives (whichever is longer) prior to the first dose of study intervention with the exception of moderate/potent CYP3A inducers which are prohibited within 14 days plus 5 half-lives prior to the first dose of study intervention. Current use of any prohibited concomitant medication(s) or those unwilling/unable to use a permitted concomitant medication(s). Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of study intervention used in this study (whichever is longer). A positive urine drug test. Screening and baseline supine blood pressure (BP) >140 mm Hg (systolic) or >90 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP is >140 mm Hg (systolic) or >90 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility. Screening and baseline standard 12 lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, baseline QTcF interval >450 msec, atrial fibrillation, complete left bundle branch block (LBBB), signs of an acute or indeterminate age myocardial infarction, ST T interval changes suggestive of myocardial ischemia, second or third degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the baseline uncorrected QT interval is >450 msec, this interval should be rate corrected using the Fridericia method and the resulting QTcF should be used for decision making and reporting. If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or QRS values should be used to determine the participant's eligibility. Computer interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding a participant. Participants with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat test, if deemed necessary: Aspartate aminotransferase (AST) or Alanine Aminotransferase (ALT) level ≥ 1.5 × ULN; Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is≤ ULN. History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5 (male) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine). Positive urine drug screen or cotinine at screening or check-in, and positive urine alcohol at check-in. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing. History of sensitivity to heparin or heparin induced thrombocytopenia. Unwilling or unable to comply with the criteria in the Lifestyle Considerations of this protocol. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members. Subjects with exposure to significant diagnostic or therapeutic radiation (eg,serial x ray, computed tomography scan, barium meal) or current employment in a job requiring radiation exposure monitoring within 12 months prior to check-in. Subjects who have participated in more than 3 radiolabeled drug studies in the last 12 months (previous study to be at least 4 months prior to check-in to the study site where exposures are known to the investigator, or 6 months prior to check-in to the study site for a radiolabeled drug study where exposures are not known to the investigator). The total 12-month exposure from this study and a maximum of 2 other previous radiolabeled studies within 4 to 12 months prior to this study will be within the Code of Federal Regulations (CFR) recommended levels considered safe, per United States (US) Title 21 CFR 361.1.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-07265803<br>PF-07265803 is a p38 inhibitor formulated for oral delivery. | Drug: PF-07265803<br>* PF-07265803 is a p38 inhibitor formulated for oral delivery.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative recovery of urinary, fecal, and total excretion of radioactivity over time expressed as percentage of total radioactive dose administered. | Total percent of dose recovered in urine and/or feces. | Predose to maximum of Day 14 | 
| Identification of the proportion of different metabolites in plasma to determine the biotransformation pathways of PF-07265803 | Percentage (% ) of total chromatographic radioactivity by identified metabolite | Predose to maximum of Day 14 | 
| Identification of the proportion of different metabolites in urine to determine the biotransformation pathways of PF-07265803 | Percentage (%) of dose in the urine by identified metabolite | Predose to maximum of Day 14 | 
| Identification of the proportion of different metabolites in feces to determine the biotransformation pathways of PF-07265803 | Percentage (%) of dose in the feces by identified metabolite | Predose to maximum of Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUClast, of PF-07265803, PF-07327859, PF-07327860, PF-07327890. | Area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (Clast) of radiolabeled PF-07265803 following oral dosing. | Pre-dose, 0.5, 1, 2,3,4,6,9,12,24,36,48,72,96, and 120 hours post-dose | 
| AUCinf of PF-07265803, PF-07327859, PF-07327860, PF-07327890. | Area under the plasma concentration-time profile from time zero extrapolated to infinite time following oral dosing of PF-07265803, PF-07327859, PF-07327860, PF-07327890. | Pre-dose, 0.5, 1, 2,3,4,6,9,12,24,36,48,72,96, and 120 hours post-dose | 
| CL/F of PF-07265803 in plasma. | Apparent clearance following dosing of radiolabeled PF-07265803. | Pre-dose, 0.5, 1, 2,3,4,6,9,12,24,36,48,72,96, and 120 hours post-dose | 
| Vz/F of PF-07265803 in plasma. | Apparent volume of distribution, estimated from terminal phase, for extravascular dosing of radiolabeled PF-07265803. | Pre-dose, 0.5, 1, 2,3,4,6,9,12,24,36,48,72,96, and 120 hours post-dose | 
| Cmax, PF-07265803, PF-07327859, PF-07327860, PF-07327890 in plasma. | Maximum plasma concentration of radiolabeled PF-07265803, PF-07327859, PF-07327860, PF-07327890 following oral dosing. | Pre-dose, 0.5, 1, 2,3,4,6,9,12,24,36,48,72,96, and 120 hours post-dose | 
| Tmax, of PF-07265803, PF-07327859, PF-07327860, PF-07327890 in plasma. | Time to Cmas following oral dosing of radiolabeled PF-07327859, PF-07327860, PF-07327890 in plasma. | Pre-dose, 0.5, 1, 2,3,4,6,9,12,24,36,48,72,96, and 120 hours post-dose | 
| t½ of PF-07265803, PF-07327859, PF-07327860, PF-07327890 in plasma. | Terminal elimination half-life following oral dosing of radiolabeled PF-07265802. | Pre-dose, 0.5, 1, 2,3,4,6,9,12,24,36,48,72,96, and 120 hours post-dose | 
| Number of participants with Adverse Events |  | Screening up through a maximum of 35 days | 
| Number of participants with abnormalities in clinical laboratory results |  | Screening up through a maximum of 35 days | 
| Number of participants with abnormalities in 12 lead electrocardiogram (ECG) | ECG abnormalities criteria include heart rate: <40bpm and >120 bpm; QT/QTcF criteria (QT interval >500 ms; QTcF interval >450 ms; or change from baseline in QTcF >30 ms). | Screening up through a maximum of 35 days | 
| Number of participants with abnormalities in vital signs |  | Screening up through a maximum of 35 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
LMNA-related DCM, Cardiomyopathy, Lamin Type A, Heart failure, ARRY-371797