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Effects of omeprazole and ritonavir on absorption and elimination of the hepatitis C virus NS5A inhibitor GSK2336805 in healthy adults
Author(s) -
Adkison Kimberly K.,
Jones Lori S.,
Lou Yu,
Gan Jianjun,
Wilfret David A.
Publication year - 2014
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.104
Subject(s) - omeprazole , cmax , ritonavir , medicine , pharmacology , pharmacokinetics , proton pump inhibitor , cyp3a , protease inhibitor (pharmacology) , oral administration , gastroenterology , viral load , virology , virus , cytochrome p450 , metabolism , antiretroviral therapy
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 C max by 18%; no marked effect was observed on t ½ . Co‐administration of GSK2336805 30 mg with ritonavir increased GSK2336805 plasma AUC (0–∞) by 52%, C max by 43%, and t ½ 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 C max 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.