Pharmacokinetic interactions of efavirenz and voriconazole in healthy volunteers.
BACKGROUND
* Efavirenz 400 mg q24 h reduces exposure to voriconazole 200 mg q12 h when the two drugs are co-administered. * Furthermore, voriconazole increases the systemic exposure of efavirenz. * Co-administration was therefore initially contraindicated.


CONCLUSIONS
* The doses of efavirenz and voriconazole can be adjusted to provide adequate exposure to both drugs when the two are co-administered, without compromising safety. * Appropriate adjustment of doses for both drugs may thus represent an alternative to a mere contraindication.


OBJECTIVE
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(tau)) and maximum concentration (C(max)), 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 AUC(tau) (-7%; 90% CI -23, 13) and increased C(max) (23%; 90% CI -1, 53), while increasing efavirenz AUC(tau) (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.
Damle
Bharat
B
Clinical Pharmacology, Pfizer Global Research and Development, New York, NY 10017, USA. bharat.damle@pfizer.com
LaBadie
Robert
R
Crownover
Penelope
P
Glue
Paul
P
D000328:Adult; D000480:Alkynes; D000935:Antifungal Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000378:metabolism / Q000493:pharmacokinetics*; D001835:Body Weight / Q000187:drug effects* / Q000502:physiology; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004812:Epidemiologic Methods; D006801:Humans; D008297:Male; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014230:Triazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D065819:Voriconazole
D000480:Alkynes; D000935:Antifungal Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004338:Drug Combinations; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C098320:efavirenz; D065819:Voriconazole