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

Abstract

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 14 C-labeled tofacitinib dose to healthy male subjects, the mean (standard deviation) total percentage of administered radioactive dose recovered was 93.9% (63.6), with 80.1% (63.6) in the urine (28.8% parent), and 13.8% (61.9) 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.

JAK2 Disease-Risk Variants Are Gain of Function and JAK Signaling Threshold Determines Innate Receptor-Induced Proinflammatory Cytokine Secretion in Macrophages

“…The inhibitors have been commonly used in other studies (32, 33). We used tofacitinib doses that were within range observed in the plasma of subjects treated with this inhibitor(34, 35). Following JAK inhibition, S. typhimurium -infected intestinal myeloid cells secreted increased pro-inflammatory IL-1β and IL-8 levels in a JAK inhibitor dose-dependent manner; a similar increase was observed in peripheral MDMs (Supplementary Fig.…”

JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

“…It has a short pharmacokinetic half-life of ϳ3 h and is rapidly absorbed (time to peak concentration is ϳ0.5 h) and eliminated (13). In a cellular setting, tofacitinib demonstrates preferential inhibition of signaling pathways associated with JAK1 and/or JAK3 (43).…”

Improved efficacy of allergen-specific immunotherapy by JAK inhibition in a murine model of allergic asthma

“…The mean terminal plasma half-life of TOFA is 3.2 hours [37] and it has been previously shown that discontinuation of TOFA after short-term treatment in vitro allows normal reactivation of lymphocytes within four days [38]. Therefore, the effect at the time point of aerosol allergen challenge cannot be attributed to the transient action of TOFA, since the last application of TOFA was given 18 days before.…”