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.
© 2014, The American College of Clinical Pharmacology.
Publication types
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Clinical Trial, Phase I
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Randomized Controlled Trial
MeSH terms
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Adolescent
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Adult
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Aged
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Antiviral Agents / administration & dosage
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Antiviral Agents / adverse effects
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Antiviral Agents / blood
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Antiviral Agents / pharmacokinetics*
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Area Under Curve
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Biotransformation
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Carbamates / administration & dosage
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Carbamates / adverse effects
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Carbamates / blood
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Carbamates / pharmacokinetics*
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Cytochrome P-450 CYP3A / metabolism*
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Cytochrome P-450 CYP3A Inhibitors / administration & dosage*
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Cytochrome P-450 CYP3A Inhibitors / adverse effects
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Drug Interactions
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Female
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Gastrointestinal Absorption*
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Half-Life
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Healthy Volunteers
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Humans
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Male
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Metabolic Clearance Rate
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Middle Aged
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New York
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Omeprazole / administration & dosage*
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Omeprazole / adverse effects
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Protease Inhibitors / administration & dosage
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Protease Inhibitors / adverse effects
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Protease Inhibitors / blood
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Protease Inhibitors / pharmacokinetics*
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Proton Pump Inhibitors / administration & dosage*
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Proton Pump Inhibitors / adverse effects
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Ritonavir / administration & dosage*
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Ritonavir / adverse effects
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Valine / administration & dosage
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Valine / adverse effects
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Valine / analogs & derivatives*
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Valine / blood
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Valine / pharmacokinetics
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
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Young Adult
Substances
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Antiviral Agents
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Carbamates
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Cytochrome P-450 CYP3A Inhibitors
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GSK2336805
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Protease Inhibitors
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Proton Pump Inhibitors
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Viral Nonstructural Proteins
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CYP3A protein, human
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Cytochrome P-450 CYP3A
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NS-5 protein, hepatitis C virus
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Valine
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Omeprazole
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Ritonavir