Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn's Disease: Analyses of Phase I and II Trials

Abstract

Background and objectives: Risankizumab is a humanized anti-interleukin-23 monoclonal antibody in development for the treatment of several inflammatory diseases. This work characterized the pharmacokinetics of risankizumab and evaluated covariates that may affect its exposures using phase I and II trial data in subjects with psoriasis and Crohn's disease.

Methods: Plasma concentration measurements from a phase I study and a phase II study in subjects with psoriasis (n = 157; single doses of 0.01-5 mg/kg intravenously, 0.25-1 mg/kg subcutaneously, and 18 mg subcutaneously, and multiple doses of 90 and 180 mg subcutaneously), and a phase II study in subjects with Crohn's disease (n = 115; doses of 200 or 600 mg intravenously every 4 weeks followed by 180 mg subcutaneously every 8 weeks) were analyzed using non-linear mixed-effects modeling. The model was qualified using bootstrap and simulation-based diagnostics.

Results: A two-compartment model with first-order absorption and elimination described the pharmacokinetics of risankizumab. Considering the body weight and baseline albumin central tendency differences between disease populations, risankizumab clearance, steady-state volume of distribution, and terminal-phase elimination half-life were estimated to be approximately 0.35 L/day, 11.7 L, and 27 days, respectively, for a typical 90-kg subject with psoriasis with an albumin level of 42 g/L, and 0.31 L/day, 8.45 L, and 22 days, respectively, for a typical 65-kg subject with Crohn's disease with an albumin level of 37 g/L. Risankizumab absolute subcutaneous bioavailability and absorption rate constant were 72% and 0.18 day^-1, respectively. Inter-individual variability for clearance was 37%.

Conclusions: Risankizumab displayed pharmacokinetic characteristics typical for an IgG1 monoclonal antibody with no apparent target-mediated disposition. Accounting for the effects of body weight and baseline albumin explained the small differences in the pharmacokinetics of risankizumab between psoriasis and Crohn's disease, with no further differences between the patient populations.

Fig. 1

Goodness-of-fit plots for the final population-pharmacokinetic model of risankizumab. a Population-predicted vs. observed risankizumab plasma concentrations; b individual-predicted vs. observed risankizumab plasma concentrations; c conditional weighted residuals vs. population-predicted concentrations; and d conditional weighted residuals vs. time after first dose

Fig. 2

Visual predictive check for the phase II psoriasis study using the final model. Solid lines represent the medians of the observed data; dashed lines represent the 5th and 95th percentiles of the observed data, together encompassing the 90% prediction interval; the shaded regions represent the 95% confidence intervals of the corresponding simulated percentiles (purple for the median and blue for the 5th and 95th percentiles); the arrows indicate the timings of the doses. SC subcutaneous, Wk week

Fig. 3

Visual predictive check for the phase II Crohn’s disease study using the final model. Solid lines represent the medians of the observed data; dashed lines represent the 5th and 95th percentiles of the observed data, together encompassing the 90% prediction interval; the shaded regions represent the 95% confidence intervals of the corresponding simulated percentiles (purple for the median and blue for the 5th and 95th percentiles); the arrows indicate the timings of the doses. IV intravenous, SC subcutaneous, q4w every 4 weeks, q8w every 8 weeks

Fig. 4

Effect of statistically significant covariates on risankizumab simulated exposures in subjects with psoriasis (left) and Crohn’s disease (right). Points represent medians and error bars represent 95% confidence intervals of the exposure ratios relative to the reference values across 200 simulation replicates, each with 500 virtual subjects. AUC area under the curve, C_max maximum plasma concentration