1. Evaluation of Pharmacokinetic Drug Interactions of the Direct-Acting Antiviral Agents Elbasvir and Grazoprevir with Pitavastatin, Rosuvastatin, Pravastatin, and Atorvastatin in Healthy Adults.
- Author
-
Caro L, Prueksaritanont T, Fandozzi CM, Feng HP, Guo Z, Wolford D, Panebianco D, Fraser IP, Levine V, Swearingen D, Butterton JR, Iwamoto M, and Yeh WW
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Adolescent, Adult, Atorvastatin pharmacokinetics, Drug Interactions, Female, Humans, Male, Middle Aged, Neoplasm Proteins metabolism, Pravastatin pharmacokinetics, Quinolines pharmacokinetics, Rosuvastatin Calcium pharmacokinetics, Young Adult, Amides pharmacokinetics, Antiviral Agents pharmacokinetics, Benzofurans pharmacokinetics, Carbamates pharmacokinetics, Cyclopropanes pharmacokinetics, Imidazoles pharmacokinetics, Quinoxalines pharmacokinetics, Sulfonamides pharmacokinetics
- Abstract
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.
- Published
- 2021
- Full Text
- View/download PDF