Mechanistic Evaluation of the Complex Drug-Drug Interactions of Maraviroc: Contribution of Cytochrome P450 3A, P-Glycoprotein and Organic Anion Transporting Polypeptide 1B1.

The aim of the present study was to quantitatively evaluate the drug-drug interactions (DDIs) of maraviroc (MVC) with various perpetrator drugs, including telaprevir (TVR), using in vitro data-informed physiologically based pharmacokinetic (PBPK) model. MVC showed significant active uptake and biliary excretion in sandwich-cultured human hepatocytes, and two-Km organic anion transporting polypeptide (OATP)1B1-mediated uptake in transfected cells (high-affinity Km ~5 μM). No measureable active uptake was noted in OATP1B3- and OATP2B1-transfceted cells. TVR inhibited OATP1B1-mediated MVC transport in vitro, and also exhibited CYP3A time-dependent inhibition (TDI) in human hepatocytes (inactivation constant, KI = 2.24 μM, and maximum inactivation rate constant, kinact = 0.0112 min-1 ). The inactivation efficiency (kinact /KI ) was approximately 34-fold lower in human hepatocytes compared to liver microsomes. A PBPK model accounting for interactions involving CYP3A, P-glycoprotein (P-gp), and OATP1B1 was developed based on in vitro mechanistic data. MVC DDIs with ketoconazole (inhibition of CYP3A and P-gp), ritonavir (inhibition of CYP3A and P-gp), efavirenz (induction of CYP3A), rifampicin (induction of CYP3A and P-gp; inhibition of OATP1B1) and TVR (inhibition of CYP3A, P-gp, and OATP1B1) were well described by the PBPK model with optimized transporter Ki values implying that OATP1B1-mediated uptake, along with CYP3A metabolism, determines the hepatic clearance of MVC; and P-gp-mediated efflux limits its intestinal absorption. In summary, MVC disposition involves intestinal P-gp/CYP3A and hepatic OATP1B1/CYP3A interplay; and TVR simultaneously inhibits these multiple mechanisms leading to a strong DDI-- about 9.5-fold increase in MVC oral exposure.