Plausible drug interaction between cyclophosphamide and voriconazole via inhibition of CYP2B6

The inhibitory activities of eight cytochrome P450 (CYP) isoenzymes for representative or suspected inhibitors of CYPs, including pesticides, were evaluated simultaneously using an in vitro cocktail incubation method to demonstrate the importance of systematic evaluation of CYP inhibitory risks in drug interaction (DI). Potent inhibition of CYP2B6 was noticeable for some azoles, including voriconazole. When voriconazole and cyclophosphamide were co-administered in mice, cyclophosphamide-induced alopecia and leukopenia were significantly suppressed by approximately 50% with increased blood concentrations of cyclophosphamide. The formation of an active metabolite of cyclophosphamide was suppressed effectively by voriconazole in the mouse liver microsomes. Surveys of adverse event reporting databases in Japan (JADER) and the U.S. (FAERS) showed that the proportional reporting ratios of neutropenia, hemorrhagic cystitis, and alopecia for cyclophosphamide, which is principally activated by CYP2B6 in humans, were mostly reduced, or tended to be reduced when azoles, including voriconazole, were prescribed in combination. It is highly likely that DIs between cyclophosphamide and azoles occur in the clinical setting. This study also suggests that more proper consideration of CYP2B6-mediated DIs is warranted. The combination of the in vitro cocktail method and a survey of adverse event reporting databases was a useful method to comprehensively detect pharmacokinetic DIs.