Disposition and safety of omapatrilat in subjects with renal impairment

Background: Omapatrilat, a vasopeptidase inhibitor, preserves natriuretic p eptides and inhibits the renin angiotensin aldosterone system by simultaneo usly inhibiting neutral endopeptidase and angiotensin-converting enzyme. Methods: Oral omapatrilat, 10 mg/d, was administered for 8 to 9 days to thr ee groups of eight subjects with varying degrees of renal function (CLCR va lues, normal > 80; mild to moderate impairment < 80 to greater than or equa l to 30; severe impairment <30 mL/min/1.73 mL(2)) and to six subjects under going maintenance hemodialysis. Omapatrilat and its metabolites (phenylmerc aptopropionic acid, S-methylomapatrilat, S-methylphenylmercaptopropionic ac id, and cyclic S-oxide-omapatrilat) were quantified in plasma by a validate d liquid chromatography/mass spectrometry method. The model, C-max or AUC(0 -T) = intercept + slope . CLCR, was tested for a possible linear correlatio n between C-max (peak plasma concentrations) or AUC(0-T) (area under plasma concentration versus time curve) and CLCR. Results: For omapatrilat and its inactive metabolites, phenylmercaptopropio nic acid, S-methylomapatrilat, and S-methylphenylmercaptopropionic acid, th e 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 rena l function. After C-max attainment, plasma concentrations declined rapidly to about 10% of C-max values. Cyclic S-oxide-omapatrilat, a potentially act ive metabolite, was undetectable at all sampling time points. Hemodialysis did not decrease circulating levels of omapatrilat. There was minimal accum ulation of omapatrilat and phenylmercaptopropionic acid and moderate accumu lation of the S-methylated metabolites. For omapatrilat and S-methylphenylm ercaptopropionic acid, neither C-max nor AUC(0-T) was CLCR dependent. Howev er, AUC(0-T) for phenylmercaptopropionic acid and both the C-max and AUC(0- T) for S-methylomapatrilat were CLCR dependent. Conclusions: The pharmacokinetics of omapatrilat, the only clinically relev ant active compound studied, was independent of CLCR. For patients with red uced renal function, adjusting initial omapatrilat dose is not suggested. H emodialysis did not significantly contribute to the clearance of omapatrila t. The long-term pharmacodynamic response to omapatrilat will dictate dose- adjustment needs.