Evaluation of Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild-to-Moderate Hypertension

H-L Hsiao, T H Langenickel, J Petruck, K Kode, S Ayalasomayajula, U Schuehly, M Greeley, P Pal, W Zhou, M F Prescott, G Sunkara, I Rajman, H-L Hsiao, T H Langenickel, J Petruck, K Kode, S Ayalasomayajula, U Schuehly, M Greeley, P Pal, W Zhou, M F Prescott, G Sunkara, I Rajman

Abstract

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open-label, three-period, single sequence study, patients with mild-to-moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (-5/-4/-4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470.

© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Mean plasma concentration profile of sildenafil (a) and N‐desmethyl‐sildenafil (b) following administration of sildenafil alone and coadministration of sildenafil and sacubitril/valsartan.
Figure 2
Figure 2
Mean plasma concentration profile of sacubitril/valsartan analytes sacubitril (a), sacubitrilat (b), and valsartan (c) following administration of sildenafil alone and coadministration of sildenafil and sacubitril/valsartan.
Figure 3
Figure 3
Change in mean ambulatory blood pressure measurements from baseline over treatment period. (a) Change in mean aSBP, (b) mean aDBP, and (c) mean aMAP measurements during sildenafil single dose treatment, sacubitril/valsartan steady state treatment, and coadministration of sacubitril/valsartan with sildenafil. aDBP, ambulatory diastolic blood pressure; aMAP, ambulatory mean arterial pressure; aSBP, ambulatory systolic blood pressure.
Figure 4
Figure 4
Change in geometric mean (95% CI) of biomarkers over various treatment periods. Change in creatinine‐indexed urine cGMP (a) and urine ANP (b) over 24‐h time period during sildenafil single dose, sacubitril/valsartan steady state treatment, and coadministration of sacubitril/valsartan and sildenafil. ANP, atrial natriuretic peptide; cGMP, cyclic guanosine monophosphate; CI, confidence interval.

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