No clinically significant effect of erythromycin or azithromycin on the pharmacokinetics of voriconazole in healthy male volunteers.
OBJECTIVE
The antibiotic erythromycin is a potent inhibitor of cytochrome P450 CYP3A4 metabolism. As CYP isozymes, including CYP3A4, are involved in the metabolism of the new triazole voriconazole, this study investigated the effects of multiple-dose erythromycin or azithromycin on the steady-state pharmacokinetics of voriconazole in healthy male subjects.


METHODS
In an open, randomized, parallel-group, single-centre study, 30 healthy male subjects aged 20-41 years received oral voriconazole 200 mg twice daily for 14 days plus either erythromycin (1 g twice daily on days 8-14), azithromycin (500 mg once daily on days 12-14) or placebo (twice daily on days 8-14). Only morning doses were administered on day 14. Plasma concentrations of voriconazole were measured up to 12 h postdose on days 7 and 14, and plasma pharmacokinetic parameters were calculated. Adverse events and standard laboratory test results were recorded before and throughout the study.


RESULTS
Comparison of the voriconazole Cmax day 14/day 7 ratio for the voriconazole + erythromycin group with that of the voriconazole + placebo group yielded a ratio of 107.7%[90% confidence interval (CI) 90.6, 128.0]; for the voriconazole + azithromycin group, the ratio was 117.5% (90% CI 98.8, 139.7). Comparison of the voriconazole AUCtau day 14/day 7 ratios of the voriconazole + erythromycin and voriconazole + azithromycin groups with that of the voriconazole + placebo group showed ratios of 101.2% (90% CI 89.1, 114.8) and 107.9% (90% CI 95.1, 122.4), respectively. For voriconazole tmax, the differences between the day 14-day 7 calculations for the voriconazole + erythromycin or the voriconazole + azithromycin groups and that of the voriconazole + placebo group were - 0.2 h (90% CI - 0.8, 0.3) and - 0.1 h (90% CI - 0.7, 0.5), respectively. None of these changes was considered clinically relevant. The study drugs were well tolerated by subjects in all groups; the most common study drug-related adverse events were visual disturbances, reported in all groups, and abdominal pain, present in the voriconazole + erythromycin group.


CONCLUSIONS
Coadministration of erythromycin or azithromycin does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner in healthy male subjects.
Purkins
Lynn
L
Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK.
Wood
Nolan
N
Ghahramani
Parviz
P
Kleinermans
Diane
D
Layton
Gary
G
Nichols
Don
D
D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D017963:Azithromycin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D004917:Erythromycin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D065819:Voriconazole
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D004338:Drug Combinations; D011743:Pyrimidines; D014230:Triazoles; D004917:Erythromycin; D017963:Azithromycin; D065819:Voriconazole