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: C(max), AUC(0-24), and AUC(0-infinity) 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 T(½), AUC(0-24), AUC(0-infinity), and increased oral clearance of voriconazole (p < 0.05, respectively). In addition, significant increases in AUC(0-24) and AUC(0-infinity) 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.

Fig. 1

Mean (± SD) voriconazole plasma concentration–time profile after single oral administration of 200 mg voriconazole in all 18 subjects with a 4-day treatment with placebo (squares) or erythromycin (black circles)

Fig. 2

Mean (± SD) voriconazole plasma concentration–time profile after single oral administration of 200 mg of voriconazole according to CYP2C19 genotypes in the placebo treatment phase. EMextensive metabolizers, HEM heterozygous extensive metabolizers, PM poor metabolizers

Fig. 3

Mean (± SD)plasma concentration–time profile of voriconazole after a single oral administration of 200 mg of voriconazole pretreated with placebo or erythromycin and association with CYP2C19 genotypes