The pharmacokinetics of perindoprilat in normal volunteers and patients: influence of age and disease state.

The purpose of the present report was to develop a pharmacokinetic model for perindoprilat based on three phase I studies including administration of oral and intravenous perindopril and administration of intravenous perindoprilat. The model was further refined using additional data collected from four phase II clinical trials including elderly volunteers and patients with hypertension, renal failure and heart failure. A two compartment pharmacokinetic model based on unbound concentration, in which perindoprilat bound to a single saturable binding site was used to analyze the intravenous data, whereas a one compartment model, also with saturable binding, was used for the oral data. The kinetics of perindoprilat were dose dependent with the apparent volume of distribution (V/F) varying from 920 L at a dose of 3.1 mg of perindoprilat to 470 L at a dose of 12.3 mg, in normal volunteers. Apparent unbound clearance (CLu/F) ranged from 59 to 110 L h(-1), showing no systematic trend with dose or from single to multiple dosing. Unbound clearance was strongly related to creatinine clearance in the patient studies and there was also a weak relationship between volume of distribution and creatinine clearance. Unbound clearance was also found to decrease with age. The binding parameters of the model were consistent with a single binding site to a protein having the characteristics of angiotensin converting enzyme (ACE).