Pharmacokinetic-Pharmacodynamic Model Relating Lisinopril Plasma Concentrations to Regional Hemodynamic Effects in Healthy Volunteers

摘要

SummaryIn 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 toCby the Hill model:E=Emax·Cγ/CE50γ+Cγ). For PCEA, the model was fitted to the data of both doses simultaneously.Emaxwas fixed at - 100%, and we obtained (mean ± SD) CE50= 1.4 ± 0.6 ng/ml and γ = 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 obtainedEmax= 45 ± 20 ml/min, CE50= 24.0 ± 12.4 ng/ml, and γ = 3.2 ± 1.3 for BAF, andEmax= -45 ± 15%, CE50= 22.0 ± 10.2 ng/ml, and γ = 3.1 ± 1.1 for BVR. Therefore, the concentration-effect relations for BVR (or BAF) and PCEA display quite different shapes (CE50, γ), which emphasizes the necessity of performing pharmacokinetic-pharmacodynamic (PK-PD) modeling on hemodynamic parameters to determine the optimal dosages of ACEIs.