(W1230-10-68) A Phase 1, Open-Label, Single-Period, Nonrandomized Study of the Pharmacokinetics, Excretion, Mass Balance and Metabolism of Oral [¹⁴C] PF-07265803 (ARRY-371797) in Healthy Male Adults

Purpose: The purpose of this phase 1 study was to assess the pharmacokinetics, excretion, mass balance, and metabolism of PF-07265803 (formerly known as ARRY-371797), an inhibitor of the α isoform of p38 mitogen-activated protein kinase, in healthy adult male participants.

Methods: This study enrolled healthy male participants ≥18 years of age with body mass index of 18–32 kg/m² and a total body weight >50 kg (110 lb). Participants were screened up to 28 days prior to dosing to determine eligibility. After enrollment, participants were administered a single oral dose of 400 mg PF-07265803 containing 100 µCi [¹⁴C]-PF-07265803. To limit the confounding effect of absorption, [¹⁴C]-PF-07265803 was administered following an overnight fast of at least 10 hours. Mass balance, pharmacokinetics, and metabolism were assessed using plasma collected pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24, 36, 48, 72, 96, and 120 hours post-dose; urine collected pre-dose, 0–6, 6–12, 12–24, 24–48, 48–72, and 72–96 hours post-dose and each subsequent 24-hour post-dose period until discharge; and feces collected pre-dose, 0–12, 12–24, 24–48, 48–72, and 72–96 hours post-dose and each subsequent 24-hour post-dose period until discharge. Inpatient stays continued until >90% radioactive dose administered was recovered, or until < 1% (total) was excreted in urine and feces within any 24-hour period for 2 consecutive days. The maximum duration of inpatient stay was expected to be 14 days. Plasma pharmacokinetic parameters were calculated for the parent drug and its metabolites using liquid chromatography coupled with tandem mass spectrometry, and total radioactivity, as measured with liquid scintillation counting, using noncompartmental analyses.

Results: The total cumulative recovery of radioactivity up to 288 hours post-dose (mean ± SD, n=6 participants) was 88.6% ± 5.1%; 74.7% ± 3.1% was recovered in feces and 14.0% ± 2.3% in urine. PF-07327859 (formed by hydrolysis of the primary amide bond) and PF-07327890 (formed from oxidative N-demethylation and hydrolysis of the primary amide bond) were the major metabolites in plasma ( >10% of total plasma radioactivity), comprising 68.3% and 12.7% of total plasma radioactivity, respectively. PF-07265803 (original form) and PF-07327860 (formed from oxidative N-demethylation and cyclization) were minor metabolites, comprising 8.5% and 2.6% of total plasma radioactivity, respectively. Urinary and fecal excretions of PF-07265803 were minor (both 1.0% of dose) and metabolites accounted for most of the drug-related material recovered. PF-07327859 was the predominant metabolite in both feces (representing 54.4% of dose) and urine (8.8%). The maximum plasma concentration (C_max) for PF-07265803 was observed 0.5 hours post-dose in all participants. For total radioactivity, C_max was observed between 0.5 to 3 hours, with a median time to reach maximum plasma concentration (T_max ) of 1-hour post-dose. Median T_max for the main metabolites were 1.0 hour for PF-07327859, 24 hours for PF-07327860, and 2.5 hours for PF-07327890. Mean terminal half-life (t_½) for PF-07265803 following oral administration was 1.7 hours. Mean terminal t_½ for total radioactivity was only reportable for 1 participant (3.2 hours). Mean terminal t_½ for PF-07327859, PF-07327860, and PF-07327890 were 5.0 hours, 14.8 hours, and 12.0 hours, respectively. Approximately 6% of radioactivity observed in plasma was comprised of parent compound based on exposure estimates (area under the concentration–time curve to last measurable concentration [AUC_last]) for PF-07265803 and total plasma radioactivity, consistent with the presence of metabolites in circulation. No participant experienced a treatment-emergent adverse event (TEAE) in the study and thus no discontinuations from study or treatment due to TEAEs, dose reductions, or temporary discontinuations due to TEAEs were reported. No clinically significant findings in laboratory evaluations, vital signs measurements, or electrocardiograms were observed.

Conclusion: Following oral administration to healthy male participants, PF-07265803 (ARRY-371797) was well tolerated. PF-07265803 was extensively metabolized, with the main circulating metabolite PF-07327859 formed through hydrolysis of the primary amide bond. The secondary major metabolite, PF-07327890, was formed via oxidative N-demethylation and hydrolysis of the primary amide bond, and a minor metabolite, PF-07327860, was formed through oxidative N-demethylation and cyclization. Overall, excretion of drug-related material occurred primarily as metabolites in the urine and feces, with minimal amounts of intact PF-02765803 found in excreta.

Acknowledgements:This study was supported by Pfizer.