The Effects Of CYP2C19 Genotypes And CYP3A4 Inhibitor Erythromycin On Voriconazole Pharmacokinetics

Background: Voriconazole (formerly known as UK-109,496) is a new second-generation triazole antifungal agent that is structurally related to fluconazole. Voriconazole undergoes an extensive oxidative metabolism involving cytochrome P450 (CYP) enzyme isoforms CYP2C19, CYP3A4, and to a lesser extent, CYP2C9. And preliminary observations suggest that CYP2C19 genotype should be evaluated as a factor in the pharmacokinetics of voriconazole and perhaps also in drug interactions or adverse events associated with voriconazole. And studies have shown that Chinese subjects possess a high frequency of polymorphism in CYP2C19, and the frequency of CYP2C19 PM in Chinese is 18%—23%, much higher than in Caucasian, which is 3%—5%. In addition, CYP3A4 is a major drug metaboliting enzyme, in vitro, CYP3A4 inhibitor erythromycin affected voriconazole metabolism.Objective: To assess the effects of CYP2C19 genotypes and CYP3A4-mediated inhibitory effects on the pharmacokinetics of the antimycotic voriconazole in Chinese subjects.Methods: The study was carried out as a single-center, open, two-way crossover clinical trial with randomly allocated period-balanced sequences. Eighteen healthy Chinese male volunteers, of whom six were CYP2C19 homozygous EMs(^*1/^*1, EMs), six were CYP2C19 heterozygous EMs (^*1/^*2 or ^*1/^*3, HEMs), and six were CYP2C19 PMs (^*2/^*2 or ^*2/^*3, PMs) accepted two treatments of a single oral dose of 200 mg voriconazole (on the morning of day 1), once administered alone, once along with a 4-day treatment (days-2 to 1) of 500 mg erythromycin (CYP3A4 inhibitor) 3 times daily. Periods were separated by a washout period of 14 days. Plasma concentrations of voriconazole were determined for 24 hours.Results: CYP2C19 genotypes: giving voriconazole 200 mg alone, T_1/2of voriconazole in PMs, HEMs and EMs were 3.72±2.12, 4.09±2.84, 8.69±5.17h(P＜0.001); C_maxWere 2.22±0.77, 2.29±0.47, 3.03±0.75μg/mL(P＞0.05); T_max were 1.25±0.69, 1.50±0.63, 1.50±0.71h(P＞0.05); AUC_0-24 were 7.05±2.99, 8.60±5.62, 24.23±11.05h·μg/mL(P＜0.001); AUC_0-8 were 7.70±2.99, 10.75±9.42, 30.95±19.20 h.μg/mL(P＜0.001). And CL_ora/F were 499±228, 452±233, 153±110 mL/min(P＜0.001) according to genotypes. The mean plasma concentrations of voriconazole were higher in PMs compared with EMs and HEMs.CYP3A4 inhibitor: compared with only voriconazole, pharmacokinetic analysis showed significant increases in C_max(2.36±0.78μg/mL vs 3.16±0.76μtg/mL, P＜0.001), AUC_0-24(12.65±10.15h·μg/mL vs 18.97±13.86h·μg/mL, P＜0.001), AUC_0-8(15.62±15.11 h·μg/mL vs 23.63±20.45h.μg/mL, P＜0.001) and decrease in CL_oral/F (381±244 mL/min vs 245±171 mL/min, P＜0.001).These changes occurred more obviously in CYP2C19 PMs and HEMs than EMs, the impact of erythromycin on voriconazole kinetics was related to inactive CYP2C19 alleles. Pharmacokinetic analysis showed significant increases in AUC_0-8(30.95±19.20 h·μg/mL vs 47.09±23.50 h·μg/mL, P=0.003), decrease in CL_oral/F (153±110 mL/min vs 93±64 mL/min, P=0.003) in CYP2C19 PMs. Pharmacokinetic analysis showed significant increases in AUC_0-8 (10.75±9.42 h·μg/mL vs 16.95±8.10 h·μg/mL, P=0.009), decrease in CL_oral/F (452±233 mL/min vs 240±125mL/min, P=0.018) in CYP2C19 HEMs. But in CYP2C19 EMs, pharmacokinetic analysis did not show significant changes, AUC_0-8(7.70±2.99 h·μg/mL vs 10.75±5.32 h·μg/mL, P=0.151), CL_oral/F (499±228 mL/min vs 375±176mL/min, P=0.080). Conclusions: Voriconazole pharmacokinetics was critically determined by CYP2C19 genotypes and also substantially influenced by CYP3A4 inhibitors such as erythromycin. Combination therapy with potent CYP3A4 inhibitors such as erythromycin might result in the higher antifungal exposure especially in CYP2C19 PMs and heterozygous EMs patients.