Population Pharmacokinetic and Exposure-Response Analyses for Efficacy and Safety of Risankizumab in Subjects with Active Crohn's Disease.

The population pharmacokinetics (PK) of risankizumab, and exposure-response relationships for efficacy and safety in subjects with Crohn's disease (CD), were characterized using data from phase 2 and 3 studies, to support dosing regimen selection. A two-compartment model with first order absorption and first order elimination adequately described risankizumab PK. Covariates including sex, baseline fecal calprotectin, corticosteroid use, baseline creatinine clearance, body weight, and baseline albumin were statistically correlated with risankizumab clearance but their impact on exposure was not clinically relevant for efficacy or safety. Exposure-response analyses showed that exposures associated with the 600 mg intravenously (IV) induction dose at week 0, 4, and 8 achieved a near maximal response for all efficacy endpoints evaluated, with negligible added benefit from the 1200 mg IV regimen. By week 52 of the maintenance treatment, trends of higher responses were observed for the exposures range associated with the 360 mg subcutaneously (SC) every 8 weeks (Q8W) regimen for most of the evaluated efficacy endpoints, particularly for the more stringent endpoints such as endoscopic remission and ulcer free endoscopy. Exposure-response analyses for safety did not identify any apparent relationship between exposure and safety. These results supported the final dose recommendation of 600 mg IV at weeks 0, 4, and 8, followed by 360 mg SC at week 12 and Q8W thereafter in subjects with CD.