The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Ritlecitinib, a Janus Kinase 3 and Tyrosine-Protein Kinase Family Inhibitor, in Humans.

Autor:	Bauman JN; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.) jonathan.bauman@pfizer.com., Doran AC; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.)., Gualtieri GM; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.)., Hee B; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.)., Strelevitz T; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.)., Cerny MA; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.)., Banfield C; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.)., Plotka A; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.)., Wang X; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.)., Purohit VS; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.)., Dowty ME; Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Cambridge, Massachusetts (M.E.D.) andGroton, Connecticut (J.N.B., A.C.D., G.M.G., B.H., T.S., M.A.C.); Clinical Pharmacology, Pfizer, Inc., Groton, Connecticut (C.B., X.W., V.S.P.); Biostatistics, Pfizer, Inc., Collegeville, Pennsylvania (A.P.).
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2024 Sep 16; Vol. 52 (10), pp. 1124-1136. Date of Electronic Publication: 2024 Sep 16.
DOI:	10.1124/dmd.124.001843
Abstrakt:	Ritlecitinib is an oral once-daily irreversible inhibitor of Janus kinase 3 and tyrosine-protein kinase family being developed for the treatment of moderate-to-severe alopecia areata. This study examined the disposition of ritlecitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite profiles. The results indicated ritlecitinib had a systemic clearance of 43.7 L/h, a steady state volume of distribution of 73.8 L, extent of absorption of 89%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 64%. An observed long terminal half-life of total radioactivity was primarily attributed to ritlecitinib binding to plasma albumin. Ritlecitinib was the main circulating drug species in plasma (∼30%), with one major pharmacologically inactive cysteine conjugated metabolite (M2) at >10%. Oxidative metabolism (fractional clearance 0.47) and glutathione-related conjugation (fractional clearance 0.24) were the primary routes of elimination for ritlecitinib with the greatest disposition of radioactivity shown in the urine (∼71%). In vitro phenotyping indicated ritlecitinib cytochrome P450 (CYP) fraction of metabolism assignments of 0.29 for CYP3A, 0.09 for CYP2C8, 0.07 for CYP1A2, and 0.02 for CYP2C9. In vitro phenotyping in recombinant human glutathione S-transferases indicated ritlecitinib was turned over by a number of cytosolic and microsomal enzyme isoforms. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of ritlecitinib, a JAK3 and TEC family kinase inhibitor for alopecia areata in humans, as well as characterization of clearance pathways and pharmacokinetics of ritlecitinib and its metabolites. As an AMS-based ADME study design, we have expanded on reporting the standard ADME endpoints, providing key pharmacokinetic parameters, such as clearance, volume of distribution, and bioavailability, allowing for a more comprehensive understanding of drug disposition. (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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