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

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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 [AUCinf]) and peak exposure (maximum concentration [Cmax]) were increased by ≈169% and ≈80.1%, respectively, in the presence of ritlecitinib. Efavirenz exposure (AUC0–72) and peak exposure (Cmax) were similar in the presence and absence of ritlecitinib coadministration. Tolbutamide pharmacokinetic parameters (AUCinf and Cmax) were not affected by multiple ritlecitinib doses. In the presence of ritlecitinib, AUCinf and Cmax of caffeine increased by ≈165% and ≈10%, respectively. AUCinf and Cmax 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 AUCinf by ≈15%. Coadministration following multiple rifampicin doses decreased AUCinf 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.

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