Impact of Renal Impairment on the Pharmacokinetics of Abrocitinib and Its Metabolites EQ

Abrocitinib, a once-daily oral Janus kinase 1 selective inhibitor, has shown efficacy and safety in previous studies for treating moderate-to-severe atopic dermatitis (AD). Abrocitinib is primarily eliminated via the liver, but its major circulating metabolites are eliminated mainly by renal excretion. In this phase 1, nonrandomized, open-label, single-dose (200 mg) study (NCT03660241), we evaluated the impact of renal impairment on the pharmacokinetics, safety, and tolerability of abrocitinib and its metabolites in 23 subjects with different degrees of renal function (ie, normal renal function, moderate impairment, and severe impairment). Active moiety exposures were calculated as the sum of unbound exposures for abrocitinib and its active metabolites. Abrocitinib exposure, expressed as adjusted geometric mean ratios (GMRs; % [90% CI]), for maximum plasma concentration (Cmax) and area under the concentration-time curve from time 0 extrapolated to infinite time (AUCinf) were 138.49 (93.74–204.61) and 182.91 (117.09–285.71), respectively, for patients with moderate renal impairment versus normal renal function, and 99.11 (57.30–171.43) and 121.32 (68.32–215.41), respectively, for patients with severe renal impairment versus normal renal function. Subjects with renal impairment had higher exposures of active moiety. The GMRs for Cmax and AUCinf were 133.87 (102.45–174.92) and 210.20 (154.60–285.80) for subjects with moderate renal impairment versus normal renal function, respectively. Corresponding values for subjects with severe renal impairment versus normal renal function were 129.49 (92.86–180.57) and 290.68 (217.39–388.69). While abrocitinib was generally safe and well tolerated, renal impairment increased exposure to abrocitinib active moiety. Dosage should be reduced by half for moderate- to-severe AD patients with moderate or severe renal impairment.