Catalina Barceló (1), Frédéric Gaspar (2), Manel Aouri (1), Alice Panchaud (2), Margalida Rotger (1), Monia Guidi (1,2), Matthias Cavassini (1), Thierry Buclin (1), Laurent A. Decosterd (1) and Chantal Csajka (1,2) and the Swiss HIV Cohort Study.
(1) University Hospital Centre of Lausanne, Switzerland, (2) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Switzerland.
Objectives: Co-formulated elvitegravir (EVG), cobicistat (COBI), tenofovir disoproxil fumarate and emtricitabine is among the preferred regimens for first-line antiretroviral therapy. This study aimed to develop a population pharmacokinetic model for EVG and COBI and identify individual factors and co-medications influencing their disposition, taking into consideration the interaction between both compounds.
Methods: Study population included 144 HIV-infected individuals who provided 186 and 167 EVG and COBI plasma concentrations respectively. First, distinct analyses were conducted for both drugs, including individual demographic, clinical and genetic factors as potential covariates (NONMEM®). Secondly, EVG and COBI interaction was evaluated through diverse inhibitory models. Simulations based on the final model were used to compare expected drug concentrations under standard and alternative dosage regimens.
Results: Clearance with between-subject variability (BSV %CV) was 7.6 L/h (16.6% CV) and volume of distribution 61 L for EVG, and respectively 15.8 L/h (43.6% CV) and 87.3 L for COBI. Concomitant administration of non-boosted atazanavir decreased EVG clearance (CL/FEVG) by 35%, likely due to UGT1A1 inhibition. Concomitant administration of non-boosted atazanavir and ritonavir-boosted darunavir decreased COBI clearance by 49%, and 28%, respectively. The final interaction model included COBI exposure (AUC0-24) on CL/FEVG. A 2 fold increase in AUCCOBI induced a 46% reduction of CL/FEVG and AUCCOBI decreased CL/FEVG BSV by 51.3%. Simulations confirmed that EVG reduced dose of 85 mg co-administered with COBI and atazanavir produces a concentration time course comparable to the standard regimen without atazanavir.
Conclusions: EVG and COBI pharmacokinetic variability appears to be mainly explained by drug-drug interactions that may be encountered in routine clinical practice. These models might serve to derive percentile reference curves or implemented in a Bayesian tool for dosage adjustment.
Reference: PAGE 25 () Abstr 5700 [www.page-meeting.org/?abstract=5700]
Poster: Drug/Disease modeling - Infection