title: Effects of omeprazole and ritonavir on absorption and elimination of the hepatitis C virus NS5A inhibitor GSK2336805 in healthy adults.
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.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Adkison
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Jones
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Gan
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wilfret
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004347:Drug Interactions; D005260:Female; D065569:Gastrointestinal Absorption; D006207:Half-Life; D064368:Healthy Volunteers; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009518:New York; D009853:Omeprazole / Q000008:administration & dosage* / Q000009:adverse effects; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D019438:Ritonavir / Q000008:administration & dosage* / Q000009:adverse effects; D014633:Valine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D009853:Omeprazole; D011480:Protease Inhibitors; D054328:Proton Pump Inhibitors; D019438:Ritonavir; D014633:Valine; D017361:Viral Nonstructural Proteins; C000595241:GSK2336805; C104464:CYP3A protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: GSK2336805; NS5A inhibitor; hepatitis C virus (HCV); omeprazole; phase I drug-drug interaction study; ritonavir