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

• Published in: British journal of clinical pharmacology Vol. 56; no. 4; pp. 395 - 406
• Main Authors: Liao, Wei‐chi, Vesterqvist, Ole, Delaney, Carol, Jemal, Mohammed, Ferreira, Irene, Ford, Neville, Swanson, Brian, Uderman, Howard
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.10.2003; Blackwell Science; Blackwell Science Inc
• Subjects: Administration, Oral; Adult; angiotensin converting enzyme; Angiotensin-Converting Enzyme Inhibitors - blood; Angiotensin-Converting Enzyme Inhibitors - pharmacokinetics; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Antihypertensive agents; Atrial Natriuretic Factor - blood; Atrial Natriuretic Factor - urine; Biological and medical sciences; blood pressure; Blood Pressure - drug effects; Cardiovascular system; Cyclic GMP - blood; Cyclic GMP - urine; Dose-Response Relationship, Drug; Double-Blind Method; Half-Life; Humans; Male; Medical sciences; Middle Aged; Neprilysin - antagonists & inhibitors; neutral endopeptidase; omapatrilat; pharmacodynamics; pharmacokinetics; Pharmacokinetics and Pharmacodynamics; Pharmacology. Drug treatments; Pyridines - blood; Pyridines - pharmacokinetics; Pyridines - pharmacology; Renin - blood; Thiazepines - blood; Thiazepines - pharmacokinetics; Thiazepines - pharmacology; vasopeptidase inhibitor; Human; blood pressure; Healthy subject; Enzyme; Toxicity; pharmacodynamics; Single dose; Oral administration; Enzyme inhibitor; vasopeptidase inhibitor; neutral endopeptidase; Dose activity relation; Multiple dose; Peptidases; angiotensin converting enzyme; Peptidyl-dipeptidase A; Endopeptidase; Phase I trial; Omapatrilat; Hydrolases; Peptidyl-dipeptidases; Antihypertensive agent; Pharmacokinetics; ACE inhibitor
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.1365-2125.2003.01888.x

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 (Cmax = 10–895 ng ml−1; tmax = 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, Cmax (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, Cmax 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.