title: Cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV genotype 1 NS3/4A protease inhibitor.
abstract: The present study describes the cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV protease inhibitor currently in phase III clinical trials. BI 201335 showed a good Caco-II permeability (8.7 × 10(-6) cm/sec) and in vitro metabolic stability (predicted hepatic clearence (CL(hep)) <19% Q(h) in all species tested). Single dose PK revealed a clearance of 17, 3.0 and 2.6 mL/min/kg in rat, monkey and dog respectively, with a corresponding oral bioavailability of 29.1, 25.5 and 35.6%. Comparative plasma and liver PK profile in rodents showed a high liver Kp in the rat (42-fold), suggesting high target tissue distribution. Simple allometry based on animal PK predicted a human oral CL/F of 168 mL/min, within two-fold of the observed value (118 mL/min) at 240 mg in healthy volunteers. Allometry of volume of distribution generated a low exponent of 0.59, and a much lower predicted Vss/F (5-fold less than observed). Several different approaches of Vss/F prediction were evaluated and compared with the value observed in human. The averaged Vss/F from preclinical animals provides the best estimation of the observed human value (169 L vs. 175 L). Corresponding human "effective" t(1/2) values were also compared. The predicted human t(1/2) based on the CL from allometry with metabolic corrections and the averaged animal Vss represented the best estimation of the clinical data (12.1 vs. 17.2 hr). The present study demonstrated that the good preclinical ADMEPK profile of BI 201335 is consistent with that observed in the clinic. While preclinical data accurately predicted the human CL, the prediction of human Vss seems to be more challenging. The averaged Vss/F from all tested preclinical animals provided the best prediction of human Vss and the resulting "effective" t(1/2).
authors: Department of Biological Sciences, Research and development, Boehringer Ingelheim Canada Ltd., Laval, Quebec, Canada. jianmin.duan@boehringer-ingleheim.com
authors: Jianmin
authors: J
authors: Duan
authors: Chan-Loi
authors: CL
authors: Yong
authors: Michel
authors: M
authors: Garneau
authors: Ma'an
authors: M
authors: Amad
authors: Gordon
authors: G
authors: Bolger
authors: Josie
authors: J
authors: De Marte
authors: Hélène
authors: H
authors: Montpetit
authors: Francois
authors: F
authors: Otis
authors: Martin
authors: M
authors: Jutras
authors: Manon
authors: M
authors: Rhéaume
authors: Peter W
authors: PW
authors: White
authors: Montse
authors: M
authors: Llinàs-Brunet
authors: Richard C
authors: RC
authors: Bethell
authors: Michael G
authors: MG
authors: Cordingley
mesh_terms: D000042:Absorption; D000621:Aminoisobutyric Acids; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000201:enzymology; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics*; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; D011804:Quinolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D007930:Leucine; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C552340:faldaprevir