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.