Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor, omapatrilat in healthy subjects

Abstract

Aims To determine the pharmacokinetics, pharmacodynamics and tolerability of omapatrilat, a vasopeptidase inhibitor, in healthy subjects. Methods The effects of oral omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple-dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days. Results In the multiple-dose study, peak plasma concentrations ( C max = 10-895 ng ml -1 ; t max = 0.5-2 h) of omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half-life (14-19 h), attaining steady state in 3-4 days. In the single-dose study, C max (1-1009 ng ml -1 ) and AUC(0, t ) (0.4-1891 ng ml -1 h) were linear but not dose proportional. In the multiple-dose study, based on weighted least-squares linear regression analyses vs dose, C max but not AUC(0, t ) was linear at the lower doses on day 10. The lowest dose of omapatrilat (2.5 mg) almost completely inhibited ( > 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose-dependently from 10.8 ± 4.1 ( ± SD) ng 24 h -1 in the placebo group to 60.0 ± 18.2 ng 24 h -1 in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single-and multiple-dose studies. Conclusions Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of omapatrilat are consistent with once-daily dosing.

Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction

“…The changes observed in the plasma and urinary biomarkers are consistent with the anticipated mechanism of action of LCZ696. The increases in urinary cGMP and ANP levels were consistent with neprilysin inhibition as reported in the previous studies . Furthermore, the significant increase in plasma cGMP levels was sustained throughout the dosing interval, indicating effective neprilysin inhibition and further supporting a bid dosing regimen in patients with HF.…”

Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual‐Acting Angiotensin Receptor—Neprilysin Inhibitor (ARNi)

“…These findings are consistent with inhibition of NEP activity. The LCZ696‐stimulated increase in cGMP peaked at 4 and 12 hours after dosing, shortly after the maximum plasma concentrations of LBQ657 were reached, and were similar to those reported with omapatrilat in healthy volunteers 15 . Marked reductions in BP would not be expected with administration of LCZ696 in normotensive healthy participants; indeed, previous studies in normotensive volunteers have shown little effect on BP of valsartan 16 or the NEP inhibitor candoxatril, 7 likely due to normal compensatory physiologic mechanisms to prevent hypotension.…”

“…The LCZ696-stimulated increase in cGMP peaked at 4 and 12 hours after dosing, shortly after the maximum plasma concentrations of LBQ657 were reached, and were similar to those reported with omapatrilat in healthy volunteers. 15 Marked reductions in BP would not be expected with administration of LCZ696 in normotensive healthy participants; indeed, previous studies in normotensive volunteers have shown little effect on BP of valsartan 16 or the NEP inhibitor candoxatril, 7 likely due to normal compensatory physiologic mechanisms to prevent hypotension. Studies in a dTGR model of Ang II− dependent hypertension 13 demonstrated sustained, dose-dependent decreases in BP following administration of LCZ696, supporting further studies of the antihypertensive efficacy of this agent in patients with hypertension.…”

“…In contrast, studies with omapatrilat suggested that the pharmacodynamic effects of NEP inhibition were delayed compared with ACE inhibition. In healthy volunteers, t max for omapatrilat was 0.5 to 2.0 hours; near complete ACE inhibition was observed by 2 hours postdose, 15 whereas peak cGMP levels (indicative of NEP inhibition) were not reached until 4 to 8 hours postdose with single‐ or multiple‐dose administration 15 , 20 . The concurrent effects of LCZ696 on NEP inhibition and AT 1 receptor blockade may have benefits for clinical efficacy.…”

Dual-Acting Angiotensin Receptor–Neprilysin Inhibition

“…After single-dose administration, omapatrilat consistently lowered mean arterial pressure at 24 h in low-renin, normal-renin, and high-renin experimental hypertension [20]. In healthy volunteers, single oral doses of omapatrilat increased urinary atrial NP and cGMP, indicating NEP inhibition, and increased plasma renin activity, indicating ACE inhibition [21]. In hypertensive patients, blood pressure lowering and vasculoprotective effects were greater than for other therapeutic classes, including ACE inhibitors and calcium channel blockers [22-24, 25•].…”