Drug Interaction of Fluvoxamine and Fluoxetine with Nevirapine in HIV-1-Infected Individuals

Objective: To evaluate the possible pharmacokinetic interactions between nevirapine and fluvoxamine or fluoxetine in patients with HIV-1 infection. Patients and methods: Patients who were using fluvoxamine or fluoxetine concomitantly were chosen from an unselected cohort (n = 173) of HIV-1-infected individuals using a nevirapine-containing regimen (study group). HIV-1-infected patients using nevirapine without fluvoxamine or fluoxetine and non-HIV-infected individuals who were using fluvoxamine and fluoxetine were included as controls. The influence of fluvoxamine and fluoxetine on the pharmacokinetics of nevirapine was investigated with a previously developed population pharmacokinetic model. Concomitant use of fluvoxamine or fluoxetine was tested independently as covariate for apparent clearance (CL/F) of nevirapine using nonlinear mixed-effect modelling (NONMEM). Furthermore, to explore the influence of nevirapine on the pharmacokinetics of fluvoxamine and fluoxetine, dose-normalised concentrations of fluvoxamine and fluoxetine from the study group were compared with those of the controls. Results: Of the 173 HIV-1-infected individuals, 14 were using fluoxetine (n = 7) or fluvoxamine (n = 7) simultaneously with nevirapine. In addition, 17 and 29 individuals were identified as controls for the fluoxetine- and fluvoxamine-group, respectively. Concomitant use of fluvoxamine resulted in a significant reduction of 33.7% in CL/F of nevirapine; this reduction in CL/F appeared to be dose-dependent. Concomitant use of fluoxetine had no influence on the pharmacokinetics of nevirapine. Conversely, nevirapine significantly lowered plasma levels of fluoxetine plus norfluoxetine (seproxetine). In contrast, no significant difference was observed in dose-normalised concentrations of fluvoxamine when the controls were compared with the study group. Conclusion: We advise that special attention is paid to HIV-1-infected individuals using a nevirapine-containing regimen and fluvoxamine or fluoxetine concomitantly, since pharmacokinetic interactions have been observed.