Clinical Pharmacology, Allergan PLC, Suite 1900, Harborside V, 185 Hudson Street, Jersey, NJ, 07311, USA.
Novartis Institutes for Biomedical Research, Translational Medicine, Novartis Pharma AG, Basel, Switzerland.
Clin Pharmacokinet. 2017 Dec;56(12):1461-1478. doi: 10.1007/s40262-017-0543-3.
Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, 1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug-drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum plasma concentration (2.0-fold) and area under the plasma concentration-time curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the plasma concentration-time curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the plasma concentration-time curves, while the area under the plasma concentration-time curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the plasma concentration-time curves of valsartan and sacubitrilat ~2.1-fold.
沙库必曲缬沙坦（LCZ696）被批准用于治疗射血分数降低的心力衰竭。沙库必曲缬沙坦的吸收和前体药物沙库必曲转化为沙库比曲拉（脑啡肽酶抑制剂）很快，沙库必曲、沙库比曲拉和缬沙坦（血管紧张素受体阻滞剂）的最大血浆浓度分别在 0.5、1.5-2.0 和 2.0-3.0 小时内达到。在剂量增加两倍的情况下，健康受试者的沙库必曲、1.9 倍的沙库比曲拉和1.7 倍的缬沙坦的血浆浓度-时间曲线下面积呈比例增加。每日两次给药多次后，沙库必曲和缬沙坦在 3 天内达到稳态最大血浆浓度，无蓄积，而沙库比曲拉蓄积约 1.6 倍。沙库必曲主要通过肾脏以沙库比曲拉的形式消除；缬沙坦主要通过胆道消除。评估了沙库必曲缬沙坦与心力衰竭患者常用药物（如呋塞米、华法林、地高辛、卡维地洛、左炔诺孕酮/炔雌醇复方、氨氯地平、奥美拉唑、氢氯噻嗪、静脉硝酸酯类、二甲双胍、他汀类药物和西地那非）的药物相互作用。与沙库必曲缬沙坦联合用药可使阿托伐他汀的最大血浆浓度（~2.0 倍）和血浆浓度-时间曲线下面积（1.3 倍）增加；然而，它并不影响辛伐他汀的药代动力学。年龄、性别或种族对沙库必曲缬沙坦的药代动力学无影响。与健康受试者相比，心力衰竭患者的沙库必曲、沙库比曲拉和缬沙坦的血浆浓度-时间曲线下面积分别高出约 1.6、2.1 和 2.3 倍。肾功能损害对沙库必曲和缬沙坦的血浆浓度-时间曲线下面积无显著影响，而沙库比曲拉的血浆浓度-时间曲线下面积与肾功能程度相关（轻度、中度、重度肾功能损害和终末期肾病分别为 1.3、2.3、2.9 和 3.3 倍）。中度肝损伤使缬沙坦和沙库比曲拉的血浆浓度-时间曲线下面积增加约 2.1 倍。
