Drug–drug interaction profile of ritlecitinib as perpetrator and victim through cytochrome P450

Aims To assess the effect of a potent cytochrome P450 (CYP) 3A inhibitor and CYP inducer on the pharmacokinetics of ritlecitinib, a JAK3/TEC family kinase inhibitor, and assess the effect of ritlecitinib on the pharmacokinetics of CYP substrates (midazolam, efavirenz, tolbutamide, caffeine and oral contraceptives [ethinyl oestradiol and levonorgestrel]) in healthy adults. Methods Seven clinical drug–drug interaction studies were analysed. Pharmacokinetic parameters for drugs as measured in blood plasma were used to estimate the drug interaction potential with ritlecitinib as a perpetrator or victim. Results Midazolam exposure (area under plasma concentration–time curve from time 0 to infinity [AUC inf ]) and peak exposure (maximum concentration [C max ]) were increased by ≈169% and ≈80.1%, respectively, in the presence of ritlecitinib. Efavirenz exposure (AUC 0–72 ) and peak exposure (C max ) were similar in the presence and absence of ritlecitinib coadministration. Tolbutamide pharmacokinetic parameters (AUC inf and C max ) were not affected by multiple ritlecitinib doses. In the presence of ritlecitinib, AUC inf and C max of caffeine increased by ≈165% and ≈10%, respectively. AUC inf and C max of ethinyl oestradiol decreased by ≈18% and ≈12%, respectively, following coadministration of multiple ritlecitinib 200 mg once‐daily doses, but no relevant change was observed following multiple 50 mg once‐daily doses. Ritlecitinib doses did not affect the pharmacokinetics of levonorgestrel. Coadministration following multiple itraconazole doses increased ritlecitinib AUC inf by ≈15%. Coadministration following multiple rifampicin doses decreased AUC inf of ritlecitinib by ≈45%. Conclusions Ritlecitinib is a moderate inhibitor of CYP3A and CYP1A2. Strong CYP inducers can reduce ritlecitinib concentrations, but not to clinically relevant levels leading to lack of benefit.