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) (P¼0.009) in the placebo and

fluconazole arms, respectively. The change in the peak nevirapine concentration in plasma (Cmax) 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, P¼0.012]. 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, P¼0.016]. 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