title: 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.
authors.affiliation: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Co., Wallingford, CT 06492, USA. yangz@bms.com
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Lisa
authors.initials: L
authors.lastname: Zadjura
authors.forename: Celia
authors.initials: C
authors.lastname: D'Arienzo
authors.forename: Anthony
authors.initials: A
authors.lastname: Marino
authors.forename: Kenneth
authors.initials: K
authors.lastname: Santone
authors.forename: Lewis
authors.initials: L
authors.lastname: Klunk
authors.forename: Douglas
authors.initials: D
authors.lastname: Greene
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
authors.forename: Richard
authors.initials: R
authors.lastname: Colonno
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Meanwell
authors.forename: Steven
authors.initials: S
authors.lastname: Hansel
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D019380:Anti-HIV Agents; C477855:BMS-378806; D015699:HIV Envelope Protein gp120; D010879:Piperazines; D003577:Cytochrome P-450 Enzyme System