Key result
Coadministration of sacubitril/valsartan reduced the AUC of furosemide (geometric mean ratio 0.72; 90% CI 0.67-0.77) without significantly affecting its pharmacodynamic effects.
Why the study?
Does sacubitril/valsartan alter the pharmacokinetics and pharmacodynamics of furosemide in healthy subjects?
Does sacubitril/valsartan alter the pharmacokinetics and pharmacodynamics of furosemide in healthy subjects?
Sacubitril/valsartan reduces the systemic exposure of furosemide but does not significantly alter its overall 24-hour diuretic effect, suggesting no need for routine furosemide dose adjustment when coadministered.
No routine furosemide dose adjustment needed with sacubitril/valsartan; extends PK/PD data to guide combination use in heart failure.
AIMS: 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. METHODS: 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. RESULTS: ) [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. CONCLUSIONS: and AUC and 24-h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects.
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Ayalasomayajula et al. (2018) studied healthy subjects (n=28). Sacubitril/valsartan vs. Furosemide alone was evaluated on Area under the plasma concentration-time curve (AUC) from time 0 to infinity for furosemide (Geometric mean ratio 0.72, 95% CI 0.67-0.77). Coadministration of sacubitril/valsartan reduced the AUC of furosemide (geometric mean ratio 0.72; 90% CI 0.67-0.77) without significantly affecting its pharmacodynamic effects.
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