Disposition and safety of omapatrilat in subjects with renal impairment

Background Omapatrilat, a vasopeptidase inhibitor, preserves natriuretic peptides and inhibits the renin angiotensin aldosterone system by simultaneously inhibiting neutral endopeptidase and angiotensinconverting 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 (CLCR 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 -methylphenylmercaptopropionic acid, and cyclic S -oxide-omapatrilat) were quantified in plasma by a validated liquid chromatography/mass spectrometry method. The model, Cmax or AUC(0-T) = intercept + slope · CLCR, was tested for a possible linear correlation between Cmax (peak plasma concentrations) or AUC(0-T) (area under plasma concentration versus time curve) and CLCR. Results For omapatrilat and its inactive metabolites, phenylmercaptopropionic acid, S -methylomapatrilat, and S -methylphenylmercaptopropionic acid, the median times to peak plasma concentrations (tmax) 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 Cmax attainment, plasma concentrations declined rapidly to about 10% of Cmax 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 metabolites. For omapatrilat and S -methylphenylmercaptopropionic acid, neither Cmax nor AUC(0-T) was CLCR dependent. However, AUC(0-T) for phenylmercaptopropionic acid and both the Cmax and AUC(0-T) for S -methylomapatrilat were CLCR dependent. Conclusions The pharmacokinetics of omapatrilat, the only clinically relevant active compound studied, was independent of CLCR. 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 dictate dose-adjustment needs. Clinical Pharmacology & Therapeutics (2000) 68, 261–269; doi: 10.1067/mcp.2000.109033