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).

Bridging In Vitro and In Vivo Metabolism and Transport of Faldaprevir in Human Using a Novel Cocultured Human Hepatocyte System, HepatoPac

“…Faldaprevir is a low-clearance drug that is metabolically very stable in vitro (Duan et al, 2012). However, the human ADME study revealed two abundant monohydroxylated metabolites, M2a and M2b, excreted in feces, accounting for ;40% of the dose, but not found in human plasma .…”

“…Faldaprevir is a low-clearance drug in humans (Duan et al, 2012) that predominantly undergoes oxidation to form two abundant hydroxylated metabolites (M2a and M2b) detected in feces at ;40% of the administered dose without exhibiting appreciable levels of circulating metabolites . To effectively investigate the interplay of faldaprevir with transporters and DMEs, it was important to select a cellular system in which sufficient levels of metabolites would be generated for this slowly metabolized drug.…”

The Liver Partition Coefficient-Corrected Inhibitory Quotient and the Pharmacokinetic-Pharmacodynamic Relationship of Directly Acting Anti-Hepatitis C Virus Agents in Humans

“…Hepatocyte and incubation medium concentrations of tested compounds were determined against a corresponding standard curve by HPLC or LC-MS-MS as described in detail in a previous publication (10). Selection of bioanalysis methods was based on compound properties, and the best experimental condition was chosen to obtain analysis precision and accuracy (coefficient of variation [CV] Ͻ 12%).…”

“…Blood samples were collected at 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h postdosing, and plasma samples from 3 animals were pooled at each time point. All animal PK data were analyzed based on the standard noncompartmental model using WinNonlin (version 3.1; Scientific Consulting, Inc., Cary, NC) as described in a previous publication (10).…”

Generating an In Vitro–In Vivo Correlation for Metabolism and Liver Enrichment of a Hepatitis C Virus Drug, Faldaprevir, Using a Rat Hepatocyte Model (HepatoPac)

“…The cell pellet and medium samples were extracted with 2Â volume of acetonitrile containing 2% formic acid and centrifuged at 16,000g for 5 minutes. Levels of faldaprevir in the medium and cell pellet were determined by LC-MS, as described previously (Duan et al, 2012b).…”