Effect of the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of a single dose of furosemide
Effect of the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of a single dose of furosemide
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DOI：
10.1111/bcp.13505
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发表时间：
2018-05-01
影响因子：
3.4
通讯作者：
Langenickel, Thomas H.
中科院分区：
文献类型：
--
作者：
Ayalasomayajula, Surya;Schuehly, Uwe;Langenickel, Thomas H.
目的沙库巴曲/缬沙坦适用于治疗心力衰竭和射血分数降低（HFrEF）。呋塞米是一种常用于治疗HFrEF的袢利尿剂，在临床实践中可与沙库巴曲/缬沙坦联合给药。沙库巴曲/缬沙坦对呋塞米的药代动力学和药效学的影响进行了评估，在这个开放的标签，两个时期，单序列studyinhealthsubjects.MethodsAll科目（n = 28）在第1阶段接受40毫克口服单剂量呋塞米，然后由2days的冲洗。第2阶段沙库比曲/缬沙坦200 mg（97/103 mg），每日2次，共5d，第6天单次联合呋塞米40 mg。收集系列血浆和尿液样本，以确定呋塞米和沙库比曲/缬沙坦的药代动力学和呋塞米的药效学。结果呋塞米与沙库巴曲/缬沙坦合用后，血浆最大浓度（Cmax）[估计几何平均值比值（Emax）]显著降低（P < 0. 05），而沙库巴曲/缬沙坦合用后，血浆最大浓度（Cmax）[估计几何平均值比值（Emax）]显著降低（P < 0. 05（90%置信区间）：0.50（0.44，0.56）]，从时间0至无穷大的血浆浓度-时间曲线下面积（AUC）[0.72（0.67，0.77）]和24 h尿速尿排泄量[0.74（0.69，0.79）]。当与沙库巴曲/缬沙坦联合给药时，呋塞米引起的0-4 h、4-8 h和0-24 h利尿分别减少了7%、21%和0.2%，而尿钠排泄分别减少了28.5%、7%和15%。ARNI与ACEI对心力衰竭患者总体死亡率和发病率影响的关键III期前瞻性比较的事后分析（PARADIGM-HF）表明，在沙库巴曲/缬沙坦组中，呋塞米的中位剂量在基线和研究结束时相似。而不显著影响其在健康受试者中的药效学作用。
AimsSacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be coadministered with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two-period, single-sequence study in healthy subjects.MethodsAll subjects (n = 28) received 40mg oral single-dose furosemide during period 1, followed by a washout of 2days. In period 2, sacubitril/valsartan 200mg (97/103mg) was administered twice daily for 5days and a single dose of 40mg furosemide was coadministered on day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and the pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated.ResultsCoadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (C-max) [estimated geometric mean ratio (90% confidence interval): 0.50 (0.44, 0.56)], area under the plasma concentration-time curve (AUC) from time 0 to infinity [0.72 (0.67, 0.77)] and 24-h urinary excretion of furosemide [0.74 (0.69, 0.79)]. When coadministered with sacubitril/valsartan, 0-4-h, 4-8-h and 0-24-h diuresis in response to furosemide was reduced by similar to 7%, 21% and 0.2%, respectively, while natriuresis was reduced by similar to 28.5%, 7% and 15%, respectively. Post hoc analysis of the pivotal phase III Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) indicated that the median furosemide dose was similar at baseline and at the end of the study in the sacubitril/valsartan group.ConclusionsSacubitril/valsartan reduced plasma C-max and AUC and 24-h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects.