Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans

Objective Our objective was to define the pharmacodynamic profile of the new dual neutral endopeptidase (NEP)/angiotensin‐converting enzyme (ACE) inhibitor AVE7688. Methods We compared the effects of single oral doses of AVE7688 (5 and 25 mg) with those of 10 mg ramipril (R10), a selective ACE inhibitor, in a placebo‐controlled crossover study in sodium‐depleted normotensive subjects. We also compared the effects of 25 mg AVE7688 with those of a renin‐angiotensin system (RAS) blockade induced by a high dose of an angiotensin II receptor antagonist (300 mg irbesartan) and a dual blockade of the RAS (150 mg irbesartan plus 10 mg ramipril) in sodium‐replete normotensive subjects by use of the same study design. The in vivo inhibition of ACE and NEP was monitored by measuring the urinary excretion of N‐acetyl‐Ser‐Asp‐Lys‐Pro (AcSDKP) and atrial natriuretic peptide (ANP), respectively. The intensity of RAS blockade was assessed by the increase in plasma active renin concentration. Results The 24‐hour urine AcSDKP cumulative excretion increased significantly more after 25 mg AVE7688 (919 nmol [95% confidence interval (CI), 803–1052 nmol], P