Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics

Upadacitinib is a selective Janus kinase 1 inhibitor being developed for the treatment of several inflammatory autoimmune diseases, including rheumatoid arthritis. Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A enzymes. This open-label, single-dose, multicenter study assessed the pharmacokinetics of upadacitinib following oral administration of a single 15-mg dose of the upadacitinib extended-release formulation in subjects with mild (n = 6) and moderate (n = 6) hepatic impairment relative to demographically matched healthy subjects (n = 6). Subjects were assigned to 1 of the 3 groups according to the Child-Pugh classification. Relative to subjects with normal hepatic function, the ratios (90% confidence intervals) of upadacitinib area under the plasma concentration-versus-time profile from time 0 to infinity (AUC_inf ) for subjects with mild and moderate hepatic impairment were 1.28 (0.91-1.79) and 1.24 (0.87-1.76), respectively. The central ratios of upadacitinib maximum observed concentration (C_max ) were 1.04 (0.77-1.39) and 1.43 (1.05-1.95) in subjects with mild and moderate hepatic impairment, respectively, compared with subjects with normal hepatic function. No clinically significant changes in vital signs or hematology measurements were observed, and no new safety events were identified in this study. These results indicate that mild and moderate hepatic impairment has no clinically relevant effect on upadacitinib pharmacokinetics.