Evaluation of Pharmacokinetic Drug Interactions of the Direct-Acting Antiviral Agents Elbasvir and Grazoprevir with Pitavastatin, Rosuvastatin, Pravastatin, and Atorvastatin in Healthy Adults.

Autor: Caro L; Merck & Co., Inc., Kenilworth, NJ, USA. Luzelena_caro@merck.com.; Merck & Co., Inc., 770 Sumneytown Pike, WP75B-110, West Point, PA, 19486, USA. Luzelena_caro@merck.com., Prueksaritanont T; Merck & Co., Inc., Kenilworth, NJ, USA.; Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand., Fandozzi CM; Merck & Co., Inc., Kenilworth, NJ, USA., Feng HP; Merck & Co., Inc., Kenilworth, NJ, USA., Guo Z; Merck & Co., Inc., Kenilworth, NJ, USA., Wolford D; Merck & Co., Inc., Kenilworth, NJ, USA., Panebianco D; Merck & Co., Inc., Kenilworth, NJ, USA., Fraser IP; Merck & Co., Inc., Kenilworth, NJ, USA.; Abide Therapeutics, San Diego, CA, USA., Levine V; Merck & Co., Inc., Kenilworth, NJ, USA., Swearingen D; Celerion Inc., Tempe, AZ, USA., Butterton JR; Merck & Co., Inc., Kenilworth, NJ, USA., Iwamoto M; Merck & Co., Inc., Kenilworth, NJ, USA., Yeh WW; Merck & Co., Inc., Kenilworth, NJ, USA.
Jazyk: angličtina
Zdroj: Clinical drug investigation [Clin Drug Investig] 2021 Feb; Vol. 41 (2), pp. 133-147.
DOI: 10.1007/s40261-020-00974-8
Abstrakt: Background: Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug-drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates.
Methods: Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg.
Results: Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated.
Conclusions: Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR.
Databáze: MEDLINE
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