Pharmacokinetic-pharmacodynamic model relating lisinopril plasma concentrations to regional hemodynamic effects in healthy volunteers.

In a previous placebo-controlled, randomized, double-blind, cross-over study performed in 6 healthy volunteers, we investigated the pharmacokinetics and pharmacodynamics of a single oral administration of two doses (5 and 20 mg) of the angiotensin-converting enzyme inhibitor (ACEI), lisinopril. The purpose of the present study was to investigate the relation between lisinopril plasma concentrations (C, ng/ml), and lisinopril-induced effects on plasma converting enzyme activity (PCEA, nmol/ml/min), brachial artery flow (BAF, ml/min), and brachial vascular resistance (BVR, mm Hg . s/ml). PCEA and BVR were expressed in percent changes from initial values and BAF was expressed in absolute values. Effects (E) were related to C by the Hill model: E = Emax . C gamma/CE50 gamma + C gamma). For PCEA, the model was fitted to the data of both doses simultaneously. Emax was fixed at -100%, and we obtained (mean +/- SD) CE50 = 1.4 +/- 0.6 ng/ml and gamma = 0.6 +/- 0.1. For BAF and BVR, the model was fitted to the data of the 20-mg dose for 5 subjects and to those of the 5-mg dose for 1 subject. We obtained Emax = 45 +/- 20 ml/min, CE50 = 24.0 +/- 12.4 ng/ml, and gamma = 3.2 +/- 1.3 for BAF, and Emax = -45 +/- 15%, CE50 = 22.0 +/- 10.2 ng/ml, and gamma = 3.1 +/- 1.1 for BVR. Therefore, the concentration-effect relations for BVR (or BAF) and PCEA display quite different shapes (CE50, gamma), which emphasizes the necessity of performing pharmacokinetic-pharmacodynamic (PK-PD) modeling on hemodynamic parameters to determine the optimal dosages of ACEIs.