Preclinical pharmacokinetics of a novel HIV‐1 attachment inhibitor BMS‐378806 and prediction of its human pharmacokinetics

Abstract BMS‐378806 is a prototype of novel HIV attachment inhibitors that block the gp120 and CD4 interaction, the first step of HIV‐1 entry into cells. The present work investigated the pharmacokinetics of BMS‐378806 in rats, dogs and monkeys and assessed its in vitro permeability and metabolism. BMS‐378806 exhibited species‐dependent oral bioavailability which was 19%–24% in rats and monkeys and 77% in dogs. In rats and monkeys, absorption was prolonged, with an apparent terminal half‐life of 2.1 and 6.5 h, respectively. In rats, linear pharmacokinetics was observed between i.v. doses of 1 and 5 mg/kg and between p.o. doses of 5 and 25 mg/kg. The total body clearance was intermediate in rats and low in dogs and monkeys. The steady‐state volume of distribution was moderate (0.4–0.6 l/kg), contributing to a short half‐life (0.3–1.2 h) after i.v. dosing. Studies in bile‐duct cannulated rats together with intraportal infusion studies revealed that the renal and hepatic clearance each accounted for 30% and 70% of the total elimination in rats, with the hepatic clearance largely being oxidative metabolism. In vitro , BMS‐378806 was not highly protein bound (44%–73%). The Caco‐2 permeability was modest (51 nm/s) and confounded by P‐glycoprotein mediated efflux transport. Both of these may contribute to the low brain penetration observed in rats (brain/plasma AUC ratio=0.06). In human liver microsomes BMS‐378806 was equally metabolized by cytochrome P450 1A2, 2D6 and 3A4 and did not inhibit major drug‐metabolizing enzymes to a significant extent. Based on in vitro and animal data, a mechanistic approach that factors in absorption and first‐pass metabolism was employed to predict the human oral bioavailability of BMS‐378806 (ca 20%). This, together with the complex Dedrick plot method, was used to simulate human oral profiles and to project an efficacious dose. These study results offer a comprehensive assessment of the developability of BMS‐378806 and provide important guidance to improving absorption and half‐life of future compounds in the series. The current studies also demonstrate the value and approaches of understanding pharmacokinetic properties in the early stage of drug discovery. Copyright © 2005 John Wiley & Sons, Ltd.