The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Tofacitinib, a Janus Kinase Inhibitor, in Humans

• Published in: Drug metabolism and disposition Vol. 42; no. 4; pp. 759 - 773
• Main Authors: Dowty, Martin E., Lin, Jinyan, Ryder, Tim F., Wang, Weiwei, Walker, Gregory S., Vaz, Alfin, Chan, Gary L., Krishnaswami, Sriram, Prakash, Chandra
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2014
• Subjects: Aryl Hydrocarbon Hydroxylases - metabolism; Biotransformation; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A - metabolism; Feces - chemistry; Female; Humans; Janus Kinases - antagonists & inhibitors; Liver - enzymology; Liver - metabolism; Magnetic Resonance Spectroscopy; Male; Metabolic Clearance Rate; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Piperidines - blood; Piperidines - metabolism; Piperidines - pharmacokinetics; Piperidines - urine; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - urine; Pyrimidines - blood; Pyrimidines - metabolism; Pyrimidines - pharmacokinetics; Pyrimidines - urine; Pyrroles - blood; Pyrroles - metabolism; Pyrroles - pharmacokinetics; Pyrroles - urine; Tandem Mass Spectrometry; TRA; DMSO; MS; HMBC; HLM; ACN; MS/MS; AUC; ARC; STAT; AUCt-; JAK; t1/2; AUC0-; LC; Tmax; AUC0-last; ke; P450; PK; LSC; CLh; HPLC
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.113.054940

Tofacitinib is a novel, oral Janus kinase inhibitor. The objectives of this study were to summarize the pharmacokinetics and metabolism of tofacitinib in humans, including clearance mechanisms. Following administration of a single 50-mg 14C-labeled tofacitinib dose to healthy male subjects, the mean (standard deviation) total percentage of administered radioactive dose recovered was 93.9% (±3.6), with 80.1% (±3.6) in the urine (28.8% parent), and 13.8% (±1.9) in feces (0.9% parent). Tofacitinib was rapidly absorbed, with plasma concentrations and total radioactivity peaking at around 1 hour after oral administration. The mean terminal phase half-life was approximately 3.2 hours for both parent drug and total radioactivity. Most (69.4%) circulating radioactivity in plasma was parent drug, with all metabolites representing less than 10% each of total circulating radioactivity. Hepatic clearance made up around 70% of total clearance, while renal clearance made up the remaining 30%. The predominant metabolic pathways of tofacitinib included oxidation of the pyrrolopyrimidine and piperidine rings, oxidation of the piperidine ring side-chain, N-demethylation and glucuronidation. Cytochrome P450 (P450) profiling indicated that tofacitinib was mainly metabolized by CYP3A4, with a smaller contribution from CYP2C19. This pharmacokinetic characterization of tofacitinib has been consistent with its clinical experience in drug-drug interaction studies.