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 mixedeffects 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. Electronic supplementary materialThe online version of this article (https ://doi.org/10.1007/s4026 2-018-0704-z) contains supplementary material, which is available to authorized users. Key PointsA robust two-compartment model with dose-and timeindependent pharmacokinetic parameters was developed to characterize the disposition of risankizumab, an antiinterleukin-23 monoclonal antibody, in subjects with plaque psoriasis and Crohn's disease.Of the factors evaluated (demographics, disease population, laboratory values, and anti-drug antibody development), only body weight and baseline albumin level were statistically correlated with risankizumab clearance. Body weight had a modest effect on risankizumab exposure while albumin had no meaningful impact.After accounting for differences in body weight and baseline albumin levels between psoriasis and Crohn's disease patient populations, no significant differences in the pharmacokinetics of ri...

Lack of Effect of 12-Week Treatment with Risankizumab on the Pharmacokinetics of Cytochrome P450 Probe Substrates in Patients with Moderate to Severe Chronic Plaque Psoriasis

“…ADA titers in the patients who were ADA positive ranged from one to 16; these low-titer ADAs did not affect risankizumab exposure based on the comparable risankizumab trough concentrations in ADA-positive and ADA-negative subjects in the study (data not shown). These results are consistent with the population pharmacokinetic analysis of risankizumab conducted using data from phase I and II studies in patients with psoriasis and Crohn's disease [13].…”

“…Blood samples for determination of risankizumab plasma concentrations and detection of risankizumab anti-drug antibody (ADA) were collected just prior to risankizumab dosing on days 8, 36, 64, 92, 105, and 204; an additional blood sample for risankizumab plasma concentrations was collected on day 98. Risankizumab plasma concentrations and ADA were measured as previously described [5,13]. Briefly, risankizumab plasma concentrations were determined using a validated, enzyme-linked immunosorbent assay method in which a polyclonal anti-risankizumab antibody was used as the capture reagent and a biotinylated anti-idiotypic risankizumab antibody was used as the detection reagent.…”

“…Phase III studies in Crohn's disease [10,11] and ulcerative colitis [12] are currently ongoing. Risankizumab exhibits linear pharmacokinetics and has an estimated elimination half-life (t ½ ) of approximately 4 weeks in patients with psoriasis [13].…”

Clinical Pharmacokinetics and Pharmacodynamics of Risankizumab in Psoriasis Patients

“…An approximately dose proportional increase in risankizumab exposure was observed following repeated administration of 90 and 180 mg subcutaneous doses in the global phase II study [17,23], and between 75 and 150 mg subcutaneous doses in the Japanese phase II/III studies [13].…”

Practical recommendations for systemic treatment in psoriasis in case of coexisting inflammatory, neurologic, infectious or malignant disorders (BETA‐PSO: Belgian Evidence‐based Treatment Advice in Psoriasis; part 2)

“…In psoriasis patients with inactive IBD, we recommend that the TNF antagonists: adalimumab, certolizumab pegol and infliximab; the IL12/23 inhibitor: ustekinumab; the IL23/p19 inhibitors: guselkumab, risankizumab and tildrakizumab; as well as the synthetic drug apremilast, and the conventional drugs, methotrexate, cyclosporine, fumarates and acitretin, can all be used as systemic treatments as they also have a beneficial or neutral effect on IBD symptoms. [15][16][17] We advise caution with use of the following anti-IL17 biological drugs: secukinumab, ixekizumab and brodalumab, to treat psoriasis patients with inactive IBD, and in those patients with a family history of IBD. 6 We also advise not using etanercept in these patients due to the possibility of a flare-up of IBD symptoms.…”