THE PHARMACOKINETICS AND PHARMACODYNAMICS OF FOSINOPRIL IN HEMODIALYSIS-PATIENTS

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 C-14-fosinoprilat (7.5 mg), oral C-14-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 t1/2 values after IV administration of C-14-fosinoprilat were 2,042 mug . ml-1, 11.3 ml . min-1, 11.0 l, 16.3 h and 28.3 h, respectively. Following oral administration of C-14-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.