Influence of pregnancy associated with HIV on the activity of OATP drug transporter in patients under treatment with Efavirenz

Abstract

The OATP transporters have significant implications for clinical practice, once they are associated with important drug-drug interactions. Based on that, the aim of the present study is to investigate the influence of pregnancy associated with HIV on the activity of OATP transporter in patients under treatment with efavirenz (EFZ) through administration of the rosuvastatin as a probe drug. The EFZ is metabolized mainly by CYP2B6 enzyme, nevertheless, other minor elimination pathways may become important in poor metabolizers of this enzyme (allele CYP2B6*6). Considering that some previous papers indicate a possible interaction between EFZ and OATP transporter, the current work is going to elucidate the potential elimination pathway for EFZ mediated by OATP in pregnant women. In order to reach this goal, in vitro-in vivo extrapolation, based on in vitro data, is going to be performed by using a physiologically based pharmacokinetic (PBPK) model. The patients under chronic use of EFZ (treatment at least for 1 month) (n=12) will be evaluated in two different moments, during the third trimester of pregnancy and post-partum. The probe drugs rosuvastatin (OATP) and bupropion (CYP2B6) will be simultaneously administered via oral (5 and 150 mg, respectively). Samples of blood will be collected at 0 (pre-dose); 0.5; 1; 2; 3; 4; 6; 8; 12 and 24 h. Samples of mother blood and umbilical cord will be collect at delivery in order to calculate the placental transfer. The concentrations of probe substrates and EFZ will be evaluated in the biological samples by liquid chromatography tandem mass spectrometry (LC-MS/MS). The pharmacokinetic profile will be correlated with the patient genotype. The second step of the work will provide information on an EFV's potential as a substrate or inhibitor for OATP transporters (OATP1B1, OATP1B3 and OATP2B1) through in vitro studies. The Km and Vmax values achieved will be used for construction of a PBPK model that aim to identify the variation sources in EFZ disposition in pregnant women population. (AU)