Merck & Co., Inc., Kenilworth, NJ, USA.
Merck & Co., Inc., 770 Sumneytown Pike, WP75B-110, West Point, PA, 19486, USA.
Clin Drug Investig. 2021 Feb;41(2):133-147. doi: 10.1007/s40261-020-00974-8.
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.
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.
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.
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.
许多感染丙型肝炎病毒的人同时患有包括高胆固醇血症在内的合并症，这些疾病需要用他汀类药物进行治疗。在这项研究中，我们评估了丙型肝炎病毒抑制剂 Elbasvir（EBR）和 Grazoprevir（GZR）与他汀类药物之间的药物相互作用潜力。匹伐他汀、瑞舒伐他汀、普伐他汀和阿托伐他汀是有机阴离子转运多肽 1B 的底物，而瑞舒伐他汀和阿托伐他汀也是乳腺癌耐药蛋白的底物。
在健康成年人中进行了三项开放标签、I 期临床试验，这些试验使用了口服 GZR 或 EBR/GZR 的多次每日剂量和单次口服他汀类药物剂量。试验 1：GZR 200mg 加匹伐他汀 10mg。试验 2：第 1 部分，GZR 200mg 加瑞舒伐他汀 10mg，然后 EBR 50mg/GZR 200mg 加瑞舒伐他汀 10mg；第 2 部分，EBR 50mg/GZR 200mg 加普伐他汀 40mg。试验 3：EBR 50mg/GZR 200mg 加阿托伐他汀 10mg。
他汀类药物对 GZR 或 EBR 的药代动力学没有明显影响。EBR/GZR 联合用药不会导致匹伐他汀或普伐他汀的暴露量发生有临床意义的变化。然而，EBR/GZR 增加了瑞舒伐他汀（126%）和阿托伐他汀（94%）的暴露量。联合使用他汀类药物加 GZR 或 EBR/GZR 通常耐受性良好。
尽管他汀类药物不会明显影响 EBR 或 GZR 的药代动力学，但 EBR/GZR 可能会影响某些他汀类药物的药代动力学，这可能是通过抑制乳腺癌耐药蛋白而不是有机阴离子转运多肽 1B 实现的。EBR/GZR 与匹伐他汀或普伐他汀联合使用时，不需要调整他汀类药物的剂量，而当与 EBR/GZR 联合使用时，应减少瑞舒伐他汀和阿托伐他汀的剂量。
