Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

Abstract

The aim was to develop a model to describe the population pharmacokinetics of nevirapine in South African human immunodeficiency virus (HIV)-infected patients who were taking nevirapine-based antiretroviral therapy concomitantly or in the absence of rifampicin-based tuberculosis therapy. Patients were divided into two groups: (1) patients receiving nevirapine-containing antiretroviral regimen (200 mg twice daily) and continuation phase rifampicin-containing tuberculosis therapy (n = 27) in whom blood samples were obtained before and not less than 14 days after they completed tuberculosis therapy; (2) patients without tuberculosis who were receiving a nevirapine-containing antiretroviral regimen for at least 3 weeks (n = 26). The population pharmacokinetics of nevirapine was described using nonlinear mixed effects modelling with NONMEM software. Based on the developed model, plasma concentration profiles after 300, 400 and 500 mg of nevirapine twice daily were simulated. Concomitant administration of rifampicin increased nevirapine oral clearance (CL/F) by 37.4% and reduced the absorption rate constant (k(a)) by almost sixfold. Rifampicin reduced the nevirapine average minimum concentration by 39%. Simulated doses of 300 mg twice daily elevated nevirapine concentrations above subtherapeutic levels in most patients, with minimum exposure above the recommended maximum concentration. The area under the concentration-time curve of 12-hydroxynevirapine was not different in the presence of rifampicin. 2-, 3- and 8-Hydroxynevirapine were not detectable (LLOQ = 0.025 mg/L). The developed model adequately describes nevirapine population pharmacokinetics in a South African population when taken with/and in the absence of rifampicin treatment. The simulations suggest that an increased dose of 300 mg twice daily would achieve adequate nevirapine concentrations in most patients during rifampicin-containing treatment for tuberculosis.