Conclusion
The totality of data indicated a lack of clinically relevant impact of risankizumab on the evaluated CYP enzymes in patients with CD/UC. Clinicaltrials: GOV: NCT04254783.
Methods
Patients with CD or UC (n = 20) received single doses of probe substrates for CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) before and after intravenous infusions of risankizumab 1800 mg once every 4 weeks for four doses. Serial blood samples were collected for determination of concentrations of the CYP probe drugs and metabolites with and without risankizumab. Trough samples for risankizumab were collected at sparse timepoints.
Objective
The objective of this study was to characterize the effects of risankizumab on the pharmacokinetics of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A substrates in patients with moderately to severely active Crohn's disease (CD) or ulcerative colitis (UC) using a cocktail approach.
Results
The point estimates and 90% confidence intervals for maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time zero to infinity (AUCinf) ratios for the CYP probe substrates administered with risankizumab versus without risankizumab were mostly within the 0.8-1.25 equivalence bounds, except for omeprazole and caffeine. While the upper 90% CI for caffeine AUCinf exceeded 1.25, the point estimate was a modest 1.13 and the Cmax ratio was well within 0.8-1.25. For omeprazole, while the lower bound of the 90% CI for AUCt (0.715) and AUCinf (0.624) extended slightly below the default equivalence limit, the exposures of its metabolite, 5-hydroxy-omeprazole, formed via CYP2C19, were comparable before and after risankizumab treatment, indicating a limited impact of risankizumab. No new safety issues were identified in this study.