Pharmaceutics
Integrating PBPK Simulation and In Vitro Pharmacodynamics to Model Efavirenz-Associated Hepatic Oxidative Stress in Pregnancy
Par Bárbara Costa, Maria João Gouveia et Nuno Vale.
Contenu en anglais
Résumé
Background
Certain antiretroviral drugs, including efavirenz, have been associated with mitochondrial and oxidative effects in hepatic cells, but quantitative translation from nominal in vitro concentrations to an in vivo effect-site concentration remains uncertain.
Methods
A hypothesis-generating physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) framework integrated simulated EFV concentration-time profiles for six pregnancy/CYP2B6 scenarios with published Hep3B MitoSOX concentration-response data fitted with the Hill–Emax model. Translational exposure was evaluated as total hepatic EFV concentration relative to the nominal in vitro concentration range and as unbound hepatic concentration approximated from total plasma concentration and fraction unbound.