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

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.