title: A pharmacokinetic-viral kinetic model describes the effect of alisporivir as monotherapy or in combination with peg-IFN on hepatitis C virologic response.
abstract: Alisporivir is a cyclophilin inhibitor with demonstrated in vitro and in vivo activity against hepatitis C virus (HCV). We estimated the antiviral effectiveness of alisporivir alone or in combination with pegylated interferon (peg-IFN) in 88 patients infected with different HCV genotypes treated for 4 weeks. The pharmacokinetics of the two drugs were modeled and used as driving functions for the viral kinetic model. Genotype was found to significantly affect peg-IFN effectiveness (ɛ = 86.3 and 99.1% for genotypes 1/4 and genotypes 2/3, respectively, P < 10(-7)) and the loss rate of infected cells (δ = 0.22 vs. 0.39 per day in genotype 1/4 and genotype 2/3 patients, respectively, P < 10(-6)). Alisporivir effectiveness was not significantly different across genotypes and was high for doses ≥600 mg q.d. We simulated virologic responses with other alisporivir dosing regimens in HCV genotype 2/3 patients using the model. Our predictions consistently matched the observed responses, demonstrating that this model could be a useful tool for anticipating virologic response and optimizing alisporivir-based therapies.
authors.affiliation: 1] IAME, UMR 1137, INSERM, Paris, France [2] IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: T H T
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: 1] IAME, UMR 1137, INSERM, Paris, France [2] IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Mentré
authors.affiliation: Novartis Pharmaceutical Corp., East Hanover, New Jersey, USA.
authors.forename: M
authors.initials: M
authors.lastname: Levi
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: 1] IAME, UMR 1137, INSERM, Paris, France [2] IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Guedj
mesh_terms: D000998:Antiviral Agents / Q000493:pharmacokinetics*; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007372:Interferons / Q000008:administration & dosage*; D008297:Male; D008954:Models, Biological
chemical_list: D000998:Antiviral Agents; D016572:Cyclosporine; D007372:Interferons; C499715:alisporivir