Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Translational Medicine, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
Br J Clin Pharmacol. 2018 May;84(5):926-936. doi: 10.1111/bcp.13505. Epub 2018 Feb 20.
Sacubitril/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.
All subjects (n = 28) received 40 mg oral single-dose furosemide during period 1, followed by a washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) was administered twice daily for 5 days and a single dose of 40 mg 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.
Coadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (C ) [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 ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 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.
Sacubitril/valsartan reduced plasma C and AUC and 24-h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects.
沙库巴曲缬沙坦用于心力衰竭和射血分数降低（HFrEF）的治疗。呋塞米是一种常用于 HFrEF 治疗的袢利尿剂，在临床实践中可能与沙库巴曲缬沙坦联合使用。本研究为开放标签、两周期、单序列研究，旨在评估沙库巴曲缬沙坦对健康受试者中单次口服呋塞米的药代动力学和药效动力学的影响。
所有受试者（n=28）在第 1 周期接受 40mg 单次口服呋塞米，然后洗脱 2 天。在第 2 周期，每日两次给予沙库巴曲缬沙坦 200mg（97/103mg），连续 5 天，并在第 6 天合用 40mg 单次剂量呋塞米。连续采集血样和尿样，以确定呋塞米和沙库巴曲缬沙坦的药代动力学参数和呋塞米的药效动力学参数。评估药代动力学参数的点估计值和 90%置信区间。
与沙库巴曲缬沙坦合用，呋塞米的最大血浆浓度（C）[估计几何均数比值（90%置信区间）：0.50（0.44，0.56）]、从 0 到无穷大的血浆浓度-时间曲线下面积（AUC）[0.72（0.67，0.77）]和 24 小时尿中呋塞米排泄量[0.74（0.69，0.79）]均降低。与沙库巴曲缬沙坦合用时，0-4h、4-8h 和 0-24h 呋塞米的尿排量分别减少约 7%、21%和 0.2%，而钠排泄量分别减少约 28.5%、7%和 15%。对关键的 III 期前瞻性比较 ARNI 与 ACEI 以确定心力衰竭中的全球死亡率和发病率影响试验（PARADIGM-HF）的事后分析表明，沙库巴曲缬沙坦组在基线和研究结束时的呋塞米中位剂量相似。
在健康受试者中，沙库巴曲缬沙坦降低了血浆 C 和 AUC 以及 24 小时尿中呋塞米的排泄量，但对其药效动力学作用无显著影响。
