One of them developed telaprevir resistance (strain M). Telaprevira protease inhibitor, acyl pyrrolidine a polymerase inhibitor and 2 candidate anti-polymerase drugs were tested. All these molecules had an IC50 < 100 nmol/L in HCV replicon and JFH1 models. Fresh PHH (fPHH) and cryopreserved PHH (cPHH) were obtained after liver resection
(Biopredic Inc, Rennes). All experiments were in triplicate or more. HCV RNA in cell culture and supernatant were measured by RT-PCR 3 days post inoculation. Results In fPHH, JFH1 lead to 3 to 4 log/μg at day 3. Using 7 different fPHH donors, only 3/39 HCVser lead to a low-level replication (log2-3) in more than one experiment. AZD6244 Using 4 different cPHH donors, 3 batches reproducibly permitted a log 4-5 viral load for 8/10 tested HCVser and for JFH1. TPV and pyrrolidine inhibited most HCVser (Genotype 1) with an IC50 which was 3 to 10-fold higher than those observed for replicon or JFH1. TPV resistance of the strain M was confirmed. The molecules A and B did not reduce the replication of any clinical strain in CPHH or in fPHH and
lead to hepatocytes necrosis. No clear relationship was found with IL28B genotype of PHH. Finally, the cellular mortality was lower for cPHH than check details forfPHH. Conclusion In the era of direct antiviral molecules, cPHH authorize a significant replication of different HCVser and reliably permit the comparison of different antiviral compounds on most natural HCV strains. A striking finding was that some compound could have an antiviral activity in artificial HCVcc models but not
in HCVser. Disclosures: Mehdi Lahmar – Employment: Vivalis/valneva The following people have nothing to disclose: Tony Durand, Patrice Bruscella, Claire Gondeau, Michel Ventura, Cyrille Feray Background: MK-5172, a reversible, non-covalent, competitive inhibitor of the hepatitis C MCE公司 virus (HCV) NS3/4A protease, is being developed for the treatment of chronic HCV infection. The aim of the study was to evaluate the potential pharmacokinetic (PK) interactions, as well as safety and tolerability of MK-5172, when co-administered with IV and oral rifampin (RIF) in healthy subjects. MK-5172 is a substrate of organic anion-transporting polypeptide (OATP) and breast cancer resistance protein (BCRP) in vitro and a CYP3A4/P-glycoprotein (P-gp) substrate in vivo. Rifampin is a potent inducer of CYP3A4/P-gp following multiple-dose administration, an inhibitor of P-gp with acute administration, and an inhibitor of OATP/BCRP. Therefore, the study also assessed the clinical significance of the OATP/BCRP and CYP3A4/P-gp pathways for MK-5172. Methods: This was an open-label, fixed-sequence, multiple-dose study in 12 healthy male and female volunteers, ages 19-55 years. In Period 1, subjects received a single intravenous (IV) dose of 600 mg RIF coadministered with a single oral dose of 200 mg MK-5172, followed by a 7-day washout.