Pharmacokinetic and Pharmacodynamic Modelling of Arterial Haemodynamic Effects of Terazosin in Healthy Volunteers

Abstract

This study aimed to investigate, in healthy volunteers, the relationship between the plasma concentrations of the alpha(1)-adrenoceptor antagonist terazosin and its effects on arterial blood pressure after a single oral administration of terazosin 2 mg. M ethods: Twenty-four healthy volunteers participated in this study. Pharmacokinetic and pharmacodynamic modeling were performed subject by subject. First, plasma concentrations were fitted according to a one-compartment model with first-order absorption and monoexponential elimination. Then the maximum drug-induced decrease (E(max)) effect compartment-model was developed to describe the pharmacodynamic relationships between systolic and diastolic blood pressure and plasma concentrations using the pharmacokinetic parameters that were previously estimated. For systolic blood pressure, E(max) was 29.9 +/- 10.6 mmHg. The corresponding value for decrease in diastolic blood pressure was 39.7 +/- 8.6 mmHg. The effects of terazosin on systolic and diastolic blood pressure could be quantified by an inhibitory E(max) effect compartment model. The obtained first-order rate constant values (0.40 +/- 0.006 h(-)(1) for systolic blood pressure and 0.47 +/- 0.012 h(-)(1) for diastolic blood pressure) were consistent with the rapid development of pharmacological effect. EC(50) (concentration of terazosin that induces an effect at 50% of E(max) values) values were similar for systolic (29.9 +/- 4.3 microg/L) and diastolic (28.7 +/- 4.0 microg/L) blood pressure. A decrease in diastolic blood pressure was the most sensitive response after oral administration of a single dose of terazosin. The direct haemodynamic effects of terazosin can be characterized by an E(max) effect compartment model.