The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients

Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous ¹⁴C-fosinoprilat (7.5 mg), oral ¹⁴C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study.Mean maximum concentration (C_max), clearance (CL), volume of distribution at steady-state (V_ss), mean residence time (MRT_iv), and t_1/2 values after IV administration of ¹⁴C-fosinoprilat were 2,042 g·ml^–1, 11.3 ml·min^–1, 11.01, 16.3 h and 28.3 h, respectively. Following oral administration of ¹⁴C-fosinopril, mean C_max, time to maximum plasma concentration (t_max), and fosinoprilat bioavailability values were 197 ng·ml^–1, 5.2 h and 29.2 %. Para-hydroxy fosinoprilat and fosinoprilat glucuronide comprised approximately 15 % and 2 % of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5 % of the administered dose. The maximum effect (E_max) model was fitted to the percentage inhibition of serum ACE activity vs. fosinoprilat concentration data in three patients. E_max ranged from 95.3 to 102.5 %, and IC₅₀ (the fosinoprilat concentration required to produce 50 % of E_max) ranged from 2.6 to 4.2 ng·ml^–1.Pharmacokinetic variables of the patients were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dosing following dialysis are unnecessary.Presented in part at the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Antonio, TX, March, 1990