Effect of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan on pharmacokinetics and pharmacodynamics of a single-dose of furosemide

Summary

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 co-administrated with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two- period, single-sequence study in healthy subjects (N=28).

Methods

All subjects received 40 mg oral single dose furosemide during period 1 followed by washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) bid was administered for 5 days and a single dose of 40 mg furosemide was co-administered on Day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated.

Results

Co-administration with sacubitril/valsartan decreased plasma C_max (estimated geometric mean ratio [90% CI]: 0.50 [0.44, 0.56]), plasma AUC_inf (0.72 [0.67, 0.77]), and 24h urinary excretion of furosemide (0.74 [0.69, 0.79]). When co-administered with sacubitril/valsartan, 0-4h, 4-8h and 0-24h 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 PARADIGM-HF study indicated that the median furosemide dose was similar at baseline and end of the study in the sacubitril/valsartan group.

Conclusions

Sacubitril/valsartan reduced plasma C_max and AUC and 24h urinary excretion of furosemide while not significantly impacting its pharmacodynamic effects in healthy subjects.

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