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

Abstract

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.