Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics

Abstract

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 (AUCinf) 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 (Cmax) 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.

Clinical Pharmacokinetics of Upadacitinib: Review of Data Relevant to the Rheumatoid Arthritis Indication

“…The upadacitinib C max central value was similar in subjects with mild hepatic impairment and 43% higher in subjects with moderate hepatic impairment than in subjects with normal hepatic function. These results indicate that mild and moderate hepatic impairment have no clinically relevant effect on upadacitinib exposures (AUC or C max ) [30].…”

“…The upadacitinib AUC central value was 28% and 24% higher in subjects with mild and moderate hepatic impairment, respectively, than in subjects with normal hepatic function (based on a conservative analysis excluding one outlier with low AUC in the moderate hepatic impairment group; Fig. 1) [30]. The upadacitinib C max central value was similar in subjects with mild hepatic impairment and 43% higher in subjects with moderate hepatic impairment than in subjects with normal hepatic function.…”

“…Demographic characteristics were similar between subjects with normal and impaired hepatic function. Treatment with upadacitinib was anticipated to be not recommended in subjects with severe hepatic impairment; therefore, the impact of severe hepatic impairment on upadacitinib pharmacokinetics was not evaluated in this study [30]. There was no statistically significant difference in upadacitinib C max or AUC values in subjects with mild and moderate hepatic impairment compared with subjects with normal hepatic function.…”

“…A dedicated open-label, single-dose study was conducted to assess the effect of mild and moderate hepatic impairment (based on the Child-Pugh classification) on upadacitinib pharmacokinetics (Study 5) [30]. Subjects were assigned to one of three groups, with the mild hepatic impairment group consisting of those individuals that met Child-Pugh category A and the moderate hepatic impairment group aligning with Child-Pugh category B.…”

Exposure–Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit–Risk Assessment in Rheumatoid Arthritis

“…21,22 Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A4 isozyme (CYP3A); ~30% of upadacitinib dose is recovered in urine and feces as metabolites. 23 Strong CYP3A inhibition by ketoconazole increased upadacitinib plasma exposures by ~75% compared with administration of upadacitinib alone. 24 In subjects with mild, moderate, and severe renal impairment, upadacitinib area under the curve (AUC) was 18%, 33%, and 44% higher than matched controls.…”