Population Pharmacokinetics of Risankizumab in Healthy Volunteers and Subjects with Moderate to Severe Plaque Psoriasis: Integrated Analyses of Phase I–III Clinical Trials

Abstract

Background and Objective: Risankizumab is an anti-interleukin (IL)-23 monoclonal antibody being developed for treatment of moderate to severe plaque psoriasis. This study provided a comprehensive analysis of risankizumab pharmacokinetics in healthy subjects and patients with plaque psoriasis using data across phase I–III clinical trials. Methods: Plasma pharmacokinetic data from 1899 subjects, including 13,123 observations, who received single or multiple intravenous or subcutaneous doses of risankizumab (0.01–5 mg/kg intravenous [IV], 200–1200 mg IV, 0.25–1 mg/kg subcutaneous [SC], and 18–300 mg SC) across the phase I–III clinical program were analyzed using a non-linear mixed-effects modeling approach. The developed model was qualified and the clinical relevance of covariates statistically correlated with risankizumab clearance (CL) was evaluated using simulation analyses. Results: Risankizumab pharmacokinetics were best described using a two-compartment model with first-order absorption and elimination. Risankizumab CL, volume of distribution at steady state (Vss), and terminal-phase elimination half-life (t½) were estimated to be approximately 0.31 L/day, 11.2 L, and 28 days, respectively, for a typical 90 kg psoriatic subject, approaching steady-state plasma exposures by week 16 of dosing. Absolute SC bioavailability (F) was 89%. Bodyweight, anti-drug antibody (ADA) titers ≥ 128 (detected in only 1% of ADA-evaluable subjects in phase III studies), baseline serum albumin, high-sensitivity C-reactive protein (hs-CRP), and serum creatinine were statistically correlated with risankizumab CL; however, they had no clinically relevant impact on exposure. Conclusion: Risankizumab is characterized by dose-proportional, bi-exponential disposition with no difference in exposure between healthy subjects and patients with psoriasis. None of the covariates identified as being statistically correlated with risankizumab CL has a clinically meaningful impact on its exposure with the proposed psoriasis clinical regimen of 150 mg administered SC at weeks 0 and 4, and every 12 weeks thereafter. ClinicalTrials.gov Identifiers: NCT01577550, NCT02054481, NCT02596217, NCT02684370, NCT02672852, NCT02684357, NCT02694523.