Pharmacodynamics and Pharmacokinetics of Omapatrilat in Heart Failure

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Abstract
The purpose of this study was to determine the pharmacodynamics and pharmacokinetics of omapatrilat, administered orally (25 mg) or intravenously (10 mg) in 19 New York Heart Association class II and class III congestive heart failure (CHF) patients versus 17 healthy controls matched for age, race, gender, and weight. The plasma concentrations of atrial natriuretic peptide (ANP) increased by approximately 20% and 30% in CHF and control subjects, respectively, at 4 hours after intravenous or oral omapatrilat administration. Similar elevation in the cyclic guanosine monophosphate concentration (25% to 35%) and ANP urinary excretion (21 ng/24 h to 22 ng/24 h) was seen in all treatment groups after omapatrilat administration. Angiotensin‐converting enzyme activity was > 90% inhibited at 4 hours after dosing and remained approximately 60% to 70% inhibited at 24 hours after dosing. The levels of endothelin‐1 and endothelin‐2 remained unchanged after oral or intravenous administration of omapatrilat. The maximal reduction in seated blood pressure compared with baseline was similar for CHF and control subjects. Clinical pharmacokinetic parameters were similar in both groups after intravenous dosing, but maximum concentration and area underthe concentration‐time curve were elevated in CHF patients compared with controls after oral dosing. Omapatrilat was well tolerated; differences in systemic exposure and metabolism between CHF patients and controls did not appear to be clinically significant.