Co-administration of fluconazole increases nevirapine concentrations in HIV-infected Ugandans.
BACKGROUND
Data from retrospective studies have suggested that there may be an interaction between fluconazole and nevirapine, increasing nevirapine concentrations and potentially leading to hepatotoxicity.


METHODS
This study was nested within a large double-blind placebo-controlled study designed to determine if primary prophylaxis with fluconazole (200 mg three times per week) could reduce cryptococcal disease [CRYPTOPRO (ISRCTN 76481529)] in HIV-infected adults in rural south-western Uganda. Detailed pharmacokinetic studies were performed on 49 participants (22 on placebo and 27 on fluconazole) who had been on fluconazole or placebo with nevirapine for > or =4 weeks.


RESULTS
The geometric mean pre-dose concentrations of nevirapine were 3865 ng/mL [95% confidence interval (95% CI) 3452-4758 ng/mL] and 5141 ng/mL (95% CI 4760-6595 ng/mL) (P = 0.009) in the placebo and fluconazole arms, respectively. The change in the peak nevirapine concentration in plasma (C(max)) was also higher in the fluconazole arm compared with the placebo arm [median 6546 (95% CI 6040-7974) versus 5126 (95% CI 4739-5773) ng/mL, P = 0.012]. Fluconazole increased the nevirapine area under the curve (AUC) from 0 to 8 h by 29% [geometric mean AUC(0-8) 46 135 (95% CI 42 432-57 173) versus 35 871 (95% CI 32 808-41 372) ng.h/mL, P = 0.016]. In the larger cohort from which the participants were drawn, co-administration of fluconazole did not increase the risk of hepatotoxicity.


CONCLUSIONS
Fluconazole led to significant increases in nevirapine exposure, but was not associated with evidence of increased hepatotoxicity.
Wakeham
Katie
K
MRC/UVRI Uganda Research Unit on AIDS, PO Box 49, Entebbe, Uganda. katie.wakeham@mrcuganda.org
Parkes-Ratanshi
Rosalind
R
Watson
Victoria
V
Ggayi
Abu-Baker
AB
Khoo
Saye
S
Lalloo
David G
DG
D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000935:Antifungal Agents / Q000008:administration & dosage*; D003453:Cryptococcosis / Q000517:prevention & control*; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D019829:Nevirapine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010919:Placebos / Q000008:administration & dosage; D010949:Plasma / Q000737:chemistry*; D014454:Uganda
D019380:Anti-HIV Agents; D000935:Antifungal Agents; D010919:Placebos; D015725:Fluconazole; D019829:Nevirapine