A pharmacokinetic-viral kinetic model describes the effect of alisporivir as monotherapy or in combination with peg-IFN on hepatitis C virologic response

Clin Pharmacol Ther. 2014 Nov;96(5):599-608. doi: 10.1038/clpt.2014.173. Epub 2014 Aug 28.

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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Antiviral Agents / pharmacokinetics*
  • Cyclosporine / administration & dosage
  • Cyclosporine / pharmacokinetics*
  • Cyclosporine / pharmacology
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Genotype
  • Hepacivirus / classification
  • Hepacivirus / drug effects*
  • Hepatitis C / drug therapy
  • Hepatitis C / virology
  • Humans
  • Interferons / administration & dosage*
  • Male
  • Models, Biological

Substances

  • Antiviral Agents
  • Cyclosporine
  • Interferons
  • alisporivir