Characterization of the Effect of Renal Impairment on Upadacitinib Pharmacokinetics

Abstract

Upadacitinib is a novel selective Janus kinase 1 inhibitor developed for treatment of rheumatoid arthritis and other autoimmune diseases. The objective of this study was to assess the pharmacokinetics and safety of a single upadacitinib dose in subjects with normal renal function and in subjects with renal impairment. A total of 24 subjects between the ages of 18 and 75 years were assigned to 1 of 4 renal function groups based on estimated glomerular filtration rate (normal, mild, moderate, severe; N = 6/group). A single 15‐mg dose of upadacitinib extended‐release formulation was administered under fasting conditions. Serial plasma and urine samples were assayed to evaluate the effect of renal impairment on upadacitinib exposure through regression analysis and analysis of covariance. The primary analysis was the regression analysis of upadacitinib exposures versus estimated glomerular filtration rate. The point estimates for upadacitinib plasma exposure ratios (90% confidence interval [CI]) in subjects with mild, moderate, and severe renal impairment were 1.18 (90%CI, 1.06–1.32), 1.33 (90%CI, 1.11–1.59), and 1.44 (90%CI, 1.14–1.82) for area under the plasma concentration–time curve and 1.06 (90%CI, 0.92–1.23), 1.11 (90%CI, 0.88–1.40), and 1.14 (90%CI, 0.84–1.56) for maximum observed plasma concentration, respectively, relative to subjects with normal renal function based on the regression analysis. The analysis of covariance categorical analysis provided consistent results. Upadacitinib was well tolerated by all subjects, and no safety issues were identified in subjects with renal impairment. Renal impairment has a limited effect on upadacitinib pharmacokinetics. This is in agreement with the known limited role of urinary excretion in upadacitinib elimination. Based on the limited impact on exposure, no dose adjustment is necessary for upadacitinib in subjects with impaired renal function.

Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics

“…In the population pharmacokinetic analyses across phase 1 to 3 studies encompassing healthy subjects and subjects with RA, baseline AST, ALT, and bilirubin had no impact on upadacitinib exposure, consistent with lack of a clinically meaningful impact of mild and moderate hepatic impairment on the upadacitinib exposure observed in this dedicated phase 1 study. In addition, the effect of renal impairment on upadacitinib exposure was similar in RA patients and non‐RA patients …”

“…Additional assessments were conducted to characterize the effect of other intrinsic factors on upadacitinib pharmacokinetics. Assessment of the effect of renal impairment on upadacitinib exposure demonstrated that upadacitinib AUC was 18%, 33%, and 44% higher in subjects with mild, moderate, and severe renal impairment, respectively, and C max was similar compared with subjects with normal renal function . In addition, population pharmacokinetic analyses demonstrated that age, weight, sex, race, and ethnicity have no clinically relevant effect on upadacitinib exposure .…”

“…In addition, the effect of renal impairment on upadacitinib exposure was similar in RA patients and non-RA patients. 14,15,29 Loss of CYP activity has been documented to correlate with reduced hepatic function in a Child-Pugh score-dependent manner. 30 Because there is a metabolic component in clearance of upadacitinib that is mediated through CYP3A4 with a minor possible contribution of CYP2D6, it was possible to assume that upadacitinib exposure may increase with reduced liver function.…”

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

“…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. 25 In subjects with mild or moderate hepatic impairment, upadacitinib AUC was < 30% higher than matched controls. 23 Upadacitinib was administered in early phase I studies and in phase II studies in the form of immediate-release formulation and in phase III studies as extended-release formulation.…”

“…Strong CYP3A inhibition by ketoconazole increased upadacitinib plasma exposures by ~75% compared with administration of upadacitinib alone . In subjects with mild, moderate, and severe renal impairment, upadacitinib area under the curve (AUC) was 18%, 33%, and 44% higher than matched controls . In subjects with mild or moderate hepatic impairment, upadacitinib AUC was < 30% higher than matched controls .…”