Inhibitory effects of CYP3A4 inhibitors voriconazole, itraconazole, and fluconazole on the pharmacokinetic profiles of ceritinib in rats by HPLC-MS/MS

Introduction: Ceritinib is a second-line drug used to treat patients with non-small cell lung cancer (NSCLC) who have acquired resistance to crizotinib. Triazole antifungals are therapeutic choices for patients with cancer to reduce the risk of opportunistic fungal infections. In this study, we investigated whether three CYP3A4 inhibitors of triazole antifungals (voriconazole, itraconazole, and fluconazole) affect the pharmacokinetics of ceritinib in rats. Methods: Ceritinib was orally administered to rats alone or in combination with voriconazole, itraconazole, or fluconazole, and its pharmacokinetic parameters across treatments were compared. The plasma concentration of ceritinib was determined using a validated HPLC-MS/MS method. Results: Co-administration of ceritinib with itraconazole significantly increased the pharmacokinetic parameters (Cmax and AUC) of ceritinib, indicating that itraconazole inhibited ceritinib metabolism and increased systemic exposure. However, no significant effects were observed when voriconazole and fluconazole were used in combination. Conclusions: This study showed that co-administration with itraconazole had a significant effect on the pharmacokinetics of ceritinib, whereas the co-administration of ceritinib with voriconazole or fluconazole had no effect. Dose adjustment of ceritinib should be reconsidered upon co-administration with itraconazole in ongoing clinical practice. Hence, our study provides useful information regarding the combination of ceritinib with the CYP3A4 inhibitors voriconazole, itraconazole, and fluconazole.