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A Study in Healthy Adult Male Participants to Assess Absorption, Distribution, Metabolism and Excretion (ADME) of Radiolabeled PF-06865571.

Phase 1
Completed
Conditions
Healthy Participants
Interventions
Drug: Oral [14C]PF-06865571
Drug: Oral PF-06865571
Drug: IV [14C]PF-06865571
Registration Number
NCT04866225
Lead Sponsor
Pfizer
Brief Summary

This study is a Phase 1, open-label, non-randomized, 2-period, fixed-sequence, single-dose study of PF-06865571 in healthy male participants to characterize the ADME properties of \[14C\]PF-06865571 following oral administration; and to evaluate the absolute oral bioavailability (F) and fraction absorbed (Fa) of PF-06865571 following oral administration of unlabeled PF-06865571 and IV administration of \[14C\]PF-06865571.

Detailed Description

Not available

Recruitment & Eligibility

Status
COMPLETED
Sex
Male
Target Recruitment
6
Inclusion Criteria
  • Male participants, 18 to 60 years of age, inclusive, at the time of signing the informed consent document.
  • Male participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac tests.
  • Participants who are nonsmoking for at least 3 months at the time of signing the informed consent document.
  • BMI of 17.5 to 30.4 kg/m2, inclusive; and a total body weight >50 kg (110 lb).
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Exclusion Criteria
  • Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
  • History of irregular bowel movements including irritable bowel syndrome or frequent episodes of diarrhea or constipation, defined by less than 1 bowel movement on average per 2 days, or lactose intolerance.
  • History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg,or HCVAb. Hepatitis B vaccination is allowed.
  • History of SARS-CoV-2 PCR or antibody (eg, IgG, IgM, etc) positive result would necessitate accompanying history of asymptomatic state for at least 6 months prior to screening.
  • Use of prescription or nonprescription drugs.
  • Previous administration with an unapproved drug within 60 days preceding the first dose of study intervention used in this study.
  • A positive urine drug test.
  • A positive urine cotinine test.
  • A positive COVID-19 (SARS-CoV-2) PCR test.
  • Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing.
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SEQUENTIAL
Arm && Interventions
GroupInterventionDescription
Study armOral PF-06865571One arm of healthy male participants administered a single oral dose of \[14C\]PF-06865571; followed by a single dose of unlabeled PF-06865571, and IV administration of \[14C\]PF-06865571 three hours later.
Study armIV [14C]PF-06865571One arm of healthy male participants administered a single oral dose of \[14C\]PF-06865571; followed by a single dose of unlabeled PF-06865571, and IV administration of \[14C\]PF-06865571 three hours later.
Study armOral [14C]PF-06865571One arm of healthy male participants administered a single oral dose of \[14C\]PF-06865571; followed by a single dose of unlabeled PF-06865571, and IV administration of \[14C\]PF-06865571 three hours later.
Primary Outcome Measures
NameTimeMethod
Total Recovery of Radioactivity in Total Excreta (Urine + Feces) as Percentage of Total Radioactive Dose of PF-06865571 AdministeredPeriod 1: Day -1 to maximum Day 21; Period 2: Day 1 to maximum Day 3

The total recovery of radioactivity in the combination of urine and feces was listed and summarized using descriptive statistics. In this outcome measure, the percentages of dose excreted in total excreta (urine + feces) in Period 1 and Period 2 were reported.

Total Recovery of Radioactivity in Urine as Percentage of Total Radioactive Dose of PF-06865571 AdministeredPeriod 1: Day -1 to maximum Day 21; Period 2: Day 1 to maximum Day 3

The total recovery of radioactivity in urine was listed and summarized using descriptive statistics. In this outcome measure, the percentages of dose excreted in urine in Period 1 and Period 2 were reported.

Total Recovery of Radioactivity in Feces as Percentage of Total Radioactive Dose of PF-06865571 AdministeredPeriod 1: Day -1 to maximum Day 21; Period 2: Day 1 to maximum Day 3

The total recovery of radioactivity in feces was listed and summarized using descriptive statistics. In this outcome measure, the percentages of dose excreted in feces in Period 1 and Period 2 were reported.

Relative Abundance (Mean Value) of Metabolites of Radiolabeled PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 3, 6, 12, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

Plasma samples were analyzed for radiolabeled PF-06865571 and its metabolites. \[14C\]PF-06865571 and the major metabolites in plasma, after oral administration of 300 mg \[14C\]PF-06865571 were identified. In this outcome measure, relative abundance of the metabolites of \[14C\]PF-06865571 in plasma based on \[14C\] quantitation was reported. The metabolites included 487, 391, 412, 556, M6 (PF-07822633), M7 (PF-07911964), 584, M1 (PF-06878236), 426, M4 (PF-06887477), 600, M5 (PF-06885984) and M2 (PF-06868609). The measure type was the mean value based on pooled sampling, which means blood samples from the 6 participants were pooled together and then analyzed as 1 sample, thus the confidence interval could not be calculated. Therefore, "Number" is selected as the Measure Type.

Relative Abundance (Mean Value) of Radiolabeled PF-06865571 in Urine in Period 1Period 1: Day -1 to maximum Day 21

Urine samples were analyzed for radiolabeled PF-06865571 and its metabolites. \[14C\]PF-06865571 and the major metabolites in urine, after oral administration of 300 mg \[14C\]PF-06865571 were identified. In this outcome measure, relative abundance of radiolabeled PF-06865571 in urine based on \[14C\] quantitation was reported. The measure type was the mean value based on pooled sampling, which means blood samples from the 6 participants were pooled together and then analyzed as 1 sample, thus the confidence interval could not be calculated. Therefore, "Number" is selected as the Measure Type.

Relative Abundance (Mean Value) of Metabolites of Radiolabeled PF-06865571 in Feces in Period 1Period 1: Day -1 to maximum Day 21

Fecal samples were analyzed for radiolabeled PF-06865571 and its metabolites. \[14C\]PF-06865571 and the major metabolites in feces, after oral administration of 300 mg \[14C\]PF-06865571 were identified. In this outcome measure, relative abundance of the metabolites of \[14C\]PF-06865571 in feces based on \[14C\] quantitation was reported. The metabolites included 487, 391, 412, 556, M6 (PF-07822633), M7 (PF-07911964), 584, M1 (PF-06878236), 426, M4 (PF-06887477), 600, M5 (PF-06885984) and M2 (PF-06868609). The measure type was the mean value based on pooled sampling, which means blood samples from the 6 participants were pooled together and then analyzed as 1 sample, thus the confidence interval could not be calculated. Therefore, "Number" is selected as the Measure Type.

Relative Abundance (Mean Value) of Radiolabeled PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

Plasma samples were analyzed for radiolabeled PF-06865571 and its metabolites. \[14C\]PF-06865571 and the major metabolites in plasma, after oral administration of 300 mg \[14C\]PF-06865571 were identified. In this outcome measure, relative abundance of radiolabeled PF-06865571 in plasma based on \[14C\] quantitation was reported. The measure type was the mean value based on pooled sampling, which means blood samples from the 6 participants were pooled together and then analyzed as 1 sample, thus the confidence interval could not be calculated. Therefore, "Number" is selected as the Measure Type.

Relative Abundance (Mean Value) of Metabolites of Radiolabeled PF-06865571 in Urine in Period 1Period 1: Day -1 to maximum Day 21

Urine samples were analyzed for radiolabeled PF-06865571 and its metabolites. \[14C\]PF-06865571 and the major metabolites in urine, after oral administration of 300 mg \[14C\]PF-06865571 were identified. In this outcome measure, relative abundance of the metabolites of \[14C\]PF-06865571 in urine based on \[14C\] quantitation was reported. The metabolites included 487, 391, 412, 556, M6 (PF-07822633), M7 (PF-07911964), 584, M1 (PF-06878236), 426, M4 (PF-06887477), 600, M5 (PF-06885984) and M2 (PF-06868609). The measure type was the mean value based on pooled sampling, which means blood samples from the 6 participants were pooled together and then analyzed as 1 sample, thus the confidence interval could not be calculated. Therefore, "Number" is selected as the Measure Type.

Relative Abundance (Mean Value) of Radiolabeled PF-06865571 in Feces in Period 1Period 1: Day -1 to maximum Day 21

Fecal samples were analyzed for radiolabeled PF-06865571 and its metabolites. \[14C\]PF-06865571 and the major metabolites in feces, after oral administration of 300 mg \[14C\]PF-06865571 were identified. In this outcome measure, relative abundance of radiolabeled PF-06865571 in feces based on \[14C\] quantitation was reported. The measure type was the mean value based on pooled sampling, which means blood samples from the 6 participants were pooled together and then analyzed as 1 sample, thus the confidence interval could not be calculated. Therefore, "Number" is selected as the Measure Type.

Secondary Outcome Measures
NameTimeMethod
Maximum Plasma Concentration (Cmax) of Total Radioactivity of [14C]PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

Cmax is defined as maximum plasma concentration. The determination method of Cmax was observing directly from data.

Area Under the Plasma Concentration-time Profile From Time Zero to Time of The Last Quantifiable Concentration (AUClast) of Total Radioactivity of [14C]PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

AUClast is defined as area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (Clast). The determination method of AUClast was linear/log trapezoidal rule.

AUClast of Intravenous (IV) Radiolabeled PF-06865571 in Plasma in Period 2Period 2: -3, 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 3, 6, 9, 13, 21, 33 and 45 hours post-dose (Day 1 to Day 3)

AUClast is defined as area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (Clast). The determination method of AUClast was linear/log trapezoidal rule.

Tmax of IV Radiolabeled PF-06865571 in Plasma in Period 2Period 2: -3, 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 3, 6, 9, 13, 21, 33 and 45 hours post-dose (Day 1 to Day 3)

Tmax is defined as time to reach maximum observed plasma concentration. The determination method of Tmax was observing directly from data as time of first occurrence.

AUCinf of Oral PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). The determination method of AUCinf was AUClast + (Clast\*/ kel), where Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, kel was the terminal phase rate constant.

t1/2 of Oral PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

Terminal elimination half-life (t1/2) was the time measured for the plasma concentration to decrease by one half. The determination method of t1/2 was loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

AUCinf of IV Radiolabeled PF-06865571 in Plasma in Period 2Period 2: -3, 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 3, 6, 9, 13, 21, 33 and 45 hours post-dose (Day 1 to Day 3)

AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). The determination method of AUCinf was AUClast + (Clast\*/ kel), where Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, kel was the terminal phase rate constant.

Systemic Clearance (CL) of IV Radiolabeled PF-06865571 in Plasma in Period 2Period 2: -3, 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 3, 6, 9, 13, 21, 33 and 45 hours post-dose (Day 1 to Day 3)

CL is a quantitative measure of the rate at which a drug substance is removed from the body. The determination method of CL was dose/AUCinf.

Steady State Volume of Distribution (Vss) of IV Radiolabeled PF-06865571 in Plasma in Period 2Period 2: -3, 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 3, 6, 9, 13, 21, 33 and 45 hours post-dose (Day 1 to Day 3)

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state.

Dose-Normalized AUCinf (AUCinf[dn]) of Oral Unlabeled PF-06865571 in Plasma in Period 2Period 2: -3, 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 3, 6, 9, 13, 21, 33 and 45 hours post-dose (Day 1 to Day 3)

AUCinf = 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). AUCinf(dn) is defined as dose normalized (to 1 mg equivalent) AUCinf, which equals to AUCinf/Dose.

AUCinf(dn) of IV Microtracer of Radiolabeled PF-06865571 in Plasma in Period 2Period 2: -3, 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 3, 6, 9, 13, 21, 33 and 45 hours post-dose (Day 1 to Day 3)

AUCinf = 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). AUCinf(dn) is defined as dose normalized (to 1 mg equivalent) AUCinf, which equals to AUCinf/Dose.

Absolute Oral Bioavailability (F) of Oral Unlabeled and IV Radiolabeled PF-06865571 for Plasma AUCinf(dn) in Period 2Period 2: -3, 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 3, 6, 9, 13, 21, 33 and 45 hours post-dose (Day 1 to Day 3)

Absolute Oral Bioavailability (F) provided information on the amount of PF-06865571 reaching the systemic circulation. F was estimated as the ratio of adjusted geometric means of dose-normalized AUCinf for oral unlabeled PF-06865571 and IV labeled 14C PF-06865571 in plasma (from Period 2 only) which was equivalent to the following equation: F = \[PF-06865571_AUCpo/\[14C\]PF-06865571_AUCiv\]×\[ \[14C\]PF-06865571_Doseiv/ PF-06865571_Dosepo\], where PF-06865571_AUCpo = AUCinf(dn) of oral unlabeled PF-06865571, \[14C\]PF-06865571_AUCiv = AUCinf(dn) of intravenous radiolabeled PF-06865571, \[14C\]PF-06865571_Doseiv = dose of intravenous radiolabeled PF-06865571, PF-06865571_Dosepo = dose of oral unlabeled PF-06865571.

Percentage of Total 14C in Urine Following Oral Administration (%14C_Urine_PO) of Radiolabeled PF-06865571 in Period 1Period 1: up to 48 hours post-dose (Day 1 to Day 3)

%14C_Urine_PO is defined as percentage of the radioactive dose administered that is excreted in the urine following oral administration. %14C_Urine_PO = Total 14C_Urine_PO/14C Dosepo × 100, where PO = orally, Total 14C_Urine_PO = total radioactivity excreted into the urine post-dose following oral administration of \[14C\]PF-06865571, 14C Dosepo = dose of 14C following oral administration of \[14C\]PF-06865571.

Percentage of Total 14C in Urine Following IV Microtracer Administration (%14C_Urine_IV) of Radiolabeled PF-06865571 in Period 2Period 2: up to 48 hours post-dose (Day 1 to Day 3)

%14C_Urine_IV is defined as percentage of the radioactive dose administered that is excreted in the urine following IV administration. %14C_Urine_IV = Total 14C _Urine_IV/14C Doseiv × 100, where IV = intravenous, Total 14C_Urine_IV = total radioactivity excreted into the urine following IV administration of \[14C\]PF 06865571, 14C Doseiv = dose of 14C following IV administration of \[14C\]PF 06865571.

Time for Cmax (Tmax) of Total Radioactivity of [14C]PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

Tmax is defined as time to reach maximum observed plasma concentration. The determination method of Tmax was observing directly from data as time of first occurrence.

Area Under the Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Total Radioactivity of [14C]PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). The determination method of AUCinf was AUClast + (Clast\*/ kel), where Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, kel was the terminal phase rate constant.

Terminal Elimination Half-life (t1/2) of Total Radioactivity of [14C]PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

Terminal elimination half-life (t1/2) was the time measured for the plasma concentration to decrease by one half. The determination method of t1/2 was loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

AUClast of Oral PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

AUClast is defined as area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (Clast). The determination method of AUClast was linear/log trapezoidal rule.

Tmax of Oral PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

Tmax is defined as time to reach maximum observed plasma concentration. The determination method of Tmax was observing directly from data as time of first occurrence.

Cmax of IV Radiolabeled PF-06865571 in Plasma in Period 2Period 2: -3, 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 3, 6, 9, 13, 21, 33 and 45 hours post-dose (Day 1 to Day 3)

Cmax is defined as maximum plasma concentration. The determination method of Cmax was observing directly from data.

Cmax of Oral PF-06865571 in Plasma in Period 1Period 1: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose (Day 1 to Day 6)

Cmax is defined as maximum plasma concentration. The determination method of Cmax was observing directly from data.

t1/2 of IV Radiolabeled PF-06865571 in Plasma in Period 2Period 2: -3, 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 3, 6, 9, 13, 21, 33 and 45 hours post-dose (Day 1 to Day 3)

Terminal elimination half-life (t1/2) was the time measured for the plasma concentration to decrease by one half. The determination method of t1/2 was loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Fraction Absorbed (Fa) for Percentage of Excretion of Total 14C in Urine for Oral and IV Radiolabeled PF-06865571Period 1 and Period 2: up to 48 hours post-dose (Day 1 to Day 3)

Determination of the Fraction Absorbed (Fa) (obtained from Periods 1 and 2) provided information on the fraction of the total PF-06865571 dose absorbed, regardless of the fate of that dose after absorption (ie, metabolism, degradation, etc). Fa was estimated as the ratio of the adjusted geometric means of % of administered radioactive dose excreted into the urine following oral and IV administration of \[14C\]PF-06865571 microtracer dose over the same collection time (up to 48 hours post dose) in Periods 1 and 2, respectively: Fa = \[% 14C_Urine_PO/% 14C_Urine_IV\].

Trial Locations

Locations (1)

Labcorp Clinical Research Unit

🇺🇸

Madison, Wisconsin, United States

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