Background: Omapatrilat, a vasopeptidase inhibitor, preserves natriuretic peptides and inhibits the renin angiotensin aldosterone system by simultaneously inhibiting neutral endopeptidase and angiotensin-converting enzyme. Methods: Oral omapatrilat, 10 mg/d, was administered for 8 to 9 days to three groups of eight subjects with varying degrees of renal function (CL(CR) values, normal ≥80; mild to moderate impairment < 80 to ≥30; severe impairment <30 mL/min/1.73 mL2) and to six subjects undergoing maintenance hemodialysis. Omapatrilat and its metabolites (phenylmercaptopropionic acid, S-methylomapatrilat, S-methylphenyl-mercaptopropionic acid, and cycic S-oxide-omapatrilat) were quantified in plasma by a validated liquid chromatography/mass spectrometry method. The model, C(max) or AUC(0-T) = intercept + slope · CL(CR), was tested for a possible linear correlation between C(max) (peak plasma concentrations) or AUC(0-T) (area under plasma concentration versus time curve) and CL(CR). Results: For omapatrilat and its inactive metabolite, phenylmercaptopropionic acid, S-methylomapatrilat, and S-methylphenylmercaptopropionic acid, the median times to peak plasma concentrations (t(max)) were 1.5 to 2, 2 to 3, 2.5 to 3.5, and 7 to 10 hours, respectively, and were independent of renal function. After C(max) attainment, plasma concentrations decided rapidly to about 10% of C(max) values. Cyclic S-oxide-omapatrilat, a potentially active metabolite, was undetectable at all sampling time points. Hemodialysis did not decrease circulating levels of omapatrilat. There was minimal accumulation of omapatrilat and phenylmercaptopropionic acid and moderate accumulation of the S-methylated metabolits. For omapatrilat and S-methylphenylmer-captopropionic acid, neither C(max) nor AUC(0-T) was CL(CR) dependent. However, AUC(0-T) for phenylmercaptopropionic acid and both the C(max) and AUC(0-T) for S-methylomapatrilat were CL(CR) dependent. Conclusions: The pharmacokinetics of omapatrilat, the only clinically relevant active compound studied, was independent of CL(CR). For patients with reduced renal function, adjusting initial omapatrilat dose is not suggested. Hemodialysis did not significantly contribute to the clearance of omapatrilat. The long-term pharmacodynamic response to omapatrilat will dilate dose-adjustment needs.
