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.

Conflict of interest statement

Ahmed A. Suleiman, Mukul Minocha, Amit Khatri, Yinuo Pang, and Ahmed A. Othman are employees of AbbVie and may hold AbbVie stock or stock options.

Figures

Fig. 1

Goodness-of-fit plots for the final risankizumab population pharmacokinetic model. Diagnostic plots of the final risankizumab final pharmacokinetic model. a Observed versus individual predicted risankizumab plasma concentrations; b observed versus population predicted risankizumab plasma concentrations; c conditional weighted residuals versus population predicted risankizumab plasma concentrations; d conditional weighted residuals versus time since first risankizumab dose. Solid lines represent lines of identity in a and b and zero conditional residuals in c and d

Fig. 2

Visual predictive checks across phase III studies in patients with psoriasis who received risankizumab 150 mg subcutaneously at weeks 0 and 4 and every 12 weeks thereafter using the final population pharmacokinetic model. The gray dots represent observed data, the lines represent observed median (solid black) and observed 5%/95% percentiles (dashed) encompassing the 90% prediction interval, and the shaded regions represent the 95% confidence intervals for the simulated median (purple) and simulated 5%/95% percentiles (blue)

Fig. 3

Impact of covariates on risankizumab exposures. Points and squares represent median values and error bars represent 95% confidence intervals of the normalized exposure ratios across 200 simulation replicates. The vertical black dashed line shows an exposure ratio of 1 relative to the reference group, and the shaded area represents the 0.8–1.25 default equivalence boundaries. ADA antidrug antibody, AUC area under the concentration–time curve between weeks 40 and 52, Cmax maximum concentration, hs–CRP high-sensitivity C-reactive protein