The effects of renal function on PK of omapatrilat

Objective: Omapatrilat, the first vasopeptidase inhibitor, inhibits both neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), is inactivated by bio-transformation of its thiol group. The PK of omapatrilat in subjects normal and reduced renal function were evaluated. Methods: Omapatrilat 10 mg was administered qd for 8 or 9 days, to 8 subjects each with normal, mild to moderate, and severe renal impairment, and 6 on hemodialysis. Plasma concentrations of omapatrilat and its putative metabolites, BMS-196087 (side chain following amide hydrolysis), BMS-198433 (S-methyl omapatrilat), BMS-225308 (S-methylated side chain), and BMS-253653 (cyclic S-oxide omapatrilat), were analyzed by LC/MS/MS after the first and last doses of omapatrilat. Cmax and AUC values for each group were pooled, and the model Cmax or AUC = intercept + slope* (CLcr) was used to evaluate their association with renal function. Results: For omapatrilat and BMS-225308, the plots showed no dependence of Cmax and AUC on CLcr. For BMS-196087, there was no dependence of Cmax on CLcr, while AUC increased as CLcr decreased. Both Cmax and AUC of BMS-198433 increased as CLcr decreased. BMS-253653 was below the limit of detection (<10 ng/mL). Conclusions: PK of omapatrilat, the only measurable pharmacologically active compound, was independent of CLcr. Dose adjustment of omapatrilat is not suggested in patients with reduced renal function.