Pharmacokinetic interactions of efavirenz and voriconazole in healthy volunteers

Abstract

AIMS: Co-administration of standard-dose voriconazole and efavirenz results in a substantial decrease in voriconazole levels, while concurrently increasing efavirenz levels. Hence, concomitant use of standard doses of these drugs was initially contraindicated. This study assessed different dose combinations of efavirenz and voriconazole, with the goal of attaining a dose combination that provides systemic exposures similar to standard-dose monotherapy with each drug. METHODS: This was an open-label, four-treatment, multiple-dose, fixed-sequence study in 16 healthy males. Steady-state pharmacokinetics were assessed following two test treatments (voriconazole 300 mg q12 h + efavirenz 300 mg q24 h and voriconazole 400 mg q12 h + efavirenz 300 mg q24 h) and compared with standard-dose monotherapy (voriconazole 200 mg q12 h or efavirenz 600 mg q24 h). RESULTS: Dose adjustment to voriconazole 300 mg q12 h with efavirenz 300 mg q24 h decreased voriconazole area under the concentration-time curve (AUC τ) and maximum concentration (Cmax), with changes of -55% [90% confidence interval (CI) -62, -45] and -36% (90% CI -49, -21), respectively, when compared with monotherapy. Voriconazole 400 mg q12 h plus efavirenz 300 mg q24 h decreased voriconazole AUCτ (-7%; 90% CI -23, 13) and increased Cmax (23%; 90% CI -1, 53), while increasing efavirenz AUCτ (17%; 90% CI 6, 29) and not changing C max when compared with the respective monotherapy regimens. No serious adverse events were observed with voriconazole plus efavirenz. CONCLUSIONS: When co-administered, voriconazole dose should be increased to 400 mg q12 h and efavirenz dose decreased to 300 mg q24 h in order to provide systemic exposures similar to standard-dose monotherapy. © 2007 Pfizer Inc.