Effects of erythromycin on voriconazole pharmacokinetics and association with CYP2C19 polymorphism

Abstract

Purpose: To assess the impacts of erythromycin on the pharmacokinetics of voriconazole and its association with CYP2C19 genotypes in healthy Chinese male subjects. Methods: A single-center, open, crossover clinical study with two treatment phases was carried out. Eighteen healthy male volunteers, including 6 CYP2C19 homozygous extensive metabolizers (EMs,*1/*1), 6 heterozygous EMs (HEMs,*1/*2 or*1/*3), and 6 CYP2C19 poor metabolizers (PMs,*2/*2 or*2/*3), were enrolled in this study. A single oral dose of 200 mg voriconazole was administrated to all subjects after 3-day pretreatment with either 500 mg erythromycin or placebo three times daily. Periods were separated by a washout period of 14 days. Serial venous blood samples were collected, and plasma concentrations of voriconazole were determined by HPLC. Results: Cmax, AUC0-24, and AUC0-∞ of voriconazole were increased significantly, while oral clearance of voriconazole was decreased significantly by erythromycin administration (p < 0.001, respectively). Compared with individuals with CYP2C19 PM genotypes, individuals with CYP2C19 EM and HEM genotypes showed significantly decreased T1/2, AUC0-24, AUC 0-∞, and increased oral clearance of voriconazole (p < 0.05, respectively). In addition, significant increases in AUC0-24 and and AUC0-∞ and decreases in oral clearance of voriconazole after erythromycin treatment were observed in CYP2C19 HEMs and PMs (p < 0.05, respectively), but not in CYP2C19 EMs. Conclusion: Both CYP2C19 genotypes and CYP3A4 inhibitor erythromycin can influence the plasma concentration of voriconazole, and erythromycin increases plasma concentration of voriconazole in a CYP2C19 genotype-dependent manner. © 2010 The Author(s).