Effects of omeprazole and ritonavir on absorption and elimination of the hepatitis C virus NS5A inhibitor GSK2336805 in healthy adults

Clin Pharmacol Drug Dev. 2014 Sep;3(5):338-45. doi: 10.1002/cpdd.104. Epub 2014 Feb 18.

Abstract

This Phase I, randomized, open-label study evaluated the gastric pH-altering effects of omeprazole, a proton pump inhibitor, and the CYP3A enzyme/P-glycoprotein (Pgp)-inhibitory effects of ritonavir, an HIV protease inhibitor, on the pharmacokinetics and safety of the hepatitis C virus (HCV) non-structural protein 5A (NS5A) inhibitor GSK2336805 in healthy male and female subjects. Co-administration of GSK2336805 60 mg with omeprazole decreased GSK2336805 plasma AUC(0-∞) by 10% and Cmax by 18%; no marked effect was observed on t½ . Co-administration of GSK2336805 30 mg with ritonavir increased GSK2336805 plasma AUC(0-∞) by 52%, Cmax by 43%, and t½ by 40%; CL/F was decreased by 34%. All adverse events were minor in intensity. The gastric acid-suppressive effect of omeprazole had minimal impact on the extent and rate of GSK2336805 absorption in vivo; therefore, GSK2336805 may be co-administered with omeprazole without concern about lower GSK2336805 exposures and compromised antiviral efficacy. The modest increases in AUC and Cmax following co-administration of GSK2336805 plus ritonavir suggest that GSK2336805 when given concomitantly with a single CYP3A/Pgp inhibiting drug will not likely require dose adjustment. Final dose recommendation will be based on GSK2336805 efficacy and safety profiles from Phase III trials in HCV-infected patients.

Keywords: GSK2336805; NS5A inhibitor; hepatitis C virus (HCV); omeprazole; phase I drug-drug interaction study; ritonavir.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / adverse effects
  • Antiviral Agents / blood
  • Antiviral Agents / pharmacokinetics*
  • Area Under Curve
  • Biotransformation
  • Carbamates / administration & dosage
  • Carbamates / adverse effects
  • Carbamates / blood
  • Carbamates / pharmacokinetics*
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors / administration & dosage*
  • Cytochrome P-450 CYP3A Inhibitors / adverse effects
  • Drug Interactions
  • Female
  • Gastrointestinal Absorption*
  • Half-Life
  • Healthy Volunteers
  • Hepacivirus / drug effects*
  • Hepacivirus / enzymology
  • Humans
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • New York
  • Omeprazole / administration & dosage*
  • Omeprazole / adverse effects
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / adverse effects
  • Protease Inhibitors / blood
  • Protease Inhibitors / pharmacokinetics*
  • Proton Pump Inhibitors / administration & dosage*
  • Proton Pump Inhibitors / adverse effects
  • Ritonavir / administration & dosage*
  • Ritonavir / adverse effects
  • Valine / administration & dosage
  • Valine / adverse effects
  • Valine / analogs & derivatives*
  • Valine / blood
  • Valine / pharmacokinetics
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism
  • Young Adult

Substances

  • Antiviral Agents
  • Carbamates
  • Cytochrome P-450 CYP3A Inhibitors
  • GSK2336805
  • Protease Inhibitors
  • Proton Pump Inhibitors
  • Viral Nonstructural Proteins
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • NS-5 protein, hepatitis C virus
  • Valine
  • Omeprazole
  • Ritonavir