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. 2023 Mar 28;25(3):32.
doi: 10.1208/s12248-023-00792-8.

Leveraging Prior Healthy Participant Pharmacokinetic Data to Evaluate the Impact of Renal and Hepatic Impairment on Ritlecitinib Pharmacokinetics

Vivek Purohit  1 , Yeamin Huh  2 , Jessica Wojciechowski  2 , Anna Plotka  3 , Stephanie Salts  4 , Jeremias Antinew  2 , Angela Dimitrova  5 , Timothy Nicholas  2
Affiliations

Leveraging Prior Healthy Participant Pharmacokinetic Data to Evaluate the Impact of Renal and Hepatic Impairment on Ritlecitinib Pharmacokinetics

Vivek Purohit et al. AAPS J. .

Abstract

Ritlecitinib is a selective, covalent, irreversible inhibitor of Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinases. Pharmacokinetics and safety of ritlecitinib in participants with hepatic (Study 1) or renal (Study 2) impairment were to be characterized from two phase I studies. Due to a study pause caused by the COVID-19 pandemic, the study 2 healthy participant (HP) cohort was not recruited; however, the demography of the severe renal impairment cohort closely matched the study 1 HP cohort. We present results from each study and two innovative approaches to utilizing available HP data as reference data for study 2: a statistical approach using analysis of variance and an in silico simulation of an HP cohort created using a population pharmacokinetics (POPPK) model derived from several ritlecitinib studies. For study 1, the observed area under the curve for 24-h dosing interval and maximum plasma concentration for HPs and their observed geometric mean ratios (participants with moderate hepatic impairment vs HPs) were within 90% prediction intervals from the POPPK simulation-based approach, thereby validating the latter approach. When applied to study 2, both the statistical and POPPK simulation approaches demonstrated that patients with renal impairment would not require ritlecitinib dose modification. In both phase I studies, ritlecitinib was generally safe and well tolerated. These analyses represent a new methodology for generating reference HP cohorts in special population studies for drugs in development with well-characterized pharmacokinetics in HPs and adequate POPPK models. TRIAL REGISTRATION: ClinicalTrials.gov NCT04037865 , NCT04016077 , NCT02309827 , NCT02684760 , and NCT02969044 .

Keywords: hepatic; population pharmacokinetics; renal; ritlecitinib.

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Conflict of interest statement

The authors are employees of Pfizer Inc. and may own shares/stock options in Pfizer Inc.

Figures

Fig. 1
Fig. 1
Simulation and analysis of an in silico cohort. AUC24, area under the plasma concentration–time curve for 24-h dosing interval; QD, once daily
See this image and copyright information in PMC

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