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 ≥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 AUC0-8 46135 (95% CI 42432-57173) versus 35871 (95% CI 32808-41372) 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.