The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans.
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% (±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.
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts (M.E.D.); Pfizer Inc., Groton, Connecticut (J.L., T.F.R., W.W., G.S.W., A.V., C.P.); and Departments of Specialty Care Clinical Affairs (G.L.C.) and Clinical Pharmacology (S.K.), Pfizer Inc., Groton, Connecticut.
Martin E
ME
Dowty
Jinyan
J
Lin
Tim F
TF
Ryder
Weiwei
W
Wang
Gregory S
GS
Walker
Alfin
A
Vaz
Gary L
GL
Chan
Sriram
S
Krishnaswami
Chandra
C
Prakash
D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010880:Piperidines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D011743:Pyrimidines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D011758:Pyrroles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D053719:Tandem Mass Spectrometry
D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D053612:Janus Kinases