Pharmacodynamics and pharmacokinetics of omapatrilat in heart failure

The purpose of this study was to determine the pharmacodynamics and pharmac okinetics of omapatrilat, administered orally (25 mg) or intravenously (10 mg) in 19 New York Heart Association class II and class III congestive hear t 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 administrati on. 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 i n all treatment groups after omapatrilat administration. Angiotensin-conver ting enzyme activity was > 90% inhibited at 4 hours after dosing and remain ed approximately 60% to 70% inhibited at 24 hours after dosing. The levels of endothelin-1 and endothelin-2 remained unchanged after oral or intraveno us administration of omapatrilat. The maximal reduction in seated blood pre ssure compared with baseline was similar for CHF and control subjects. Clin ical pharmacokinetic parameters were similar in both groups after intraveno us dosing, but maximum concentration and area under the concentration-time curve were elevated in CBF patients compared with controls after oral dosin g. Omapatrilat was well tolerated; differences in systemic exposure and met abolism between CHF patients and controls did not appear to be clinically s ignificant. (C) 2001 the American College of Clinical Pharmacology.