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

• Published in: Clinical drug investigation Vol. 28; no. 3; pp. 139 - 147
• Main Authors: Campanero, Miguel Angel, Sádaba, Belén, Muñoz- Juarez, Maria José, Quetglas, Emilio García, Azanza, Jose Ramón
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.01.2008; Wolters Kluwer Health, Inc
• Subjects: Abdominal Pain - chemically induced; Administration, Oral; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists - administration & dosage; Adrenergic alpha-Antagonists - pharmacokinetics; Adrenergic alpha-Antagonists - pharmacology; Adult; Algorithms; Area Under Curve; Blood Pressure - drug effects; Chromatography, High Pressure Liquid; Dizziness - chemically induced; Dose-Response Relationship, Drug; Female; Half-Life; Headache - chemically induced; Heart Rate - drug effects; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Prazosin - analogs & derivatives; Prazosin - blood; Prazosin - pharmacokinetics; Prazosin - pharmacology; Tachycardia - chemically induced; Time Factors; Prazosin; Terazosin; Pharmacodynamic Parameter; Systolic Blood Pressure; Diastolic Blood Pressure
• ISSN: 1173-2563; 1179-1918
• DOI: 10.2165/00044011-200828030-00001

Objective: This study aimed to investigate, in healthy volunteers, the relationship between the plasma concentrations of the α 1 -adrenoceptor antagonist terazosin and its effects on arterial blood pressure after a single oral administration of terazosin 2 mg. Methods: 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. Results: For systolic blood pressure, Emax 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 −l for systolic blood pressure and 0.47 ± 0.012 h −l for diastolic blood pressure) were consistent with the rapid development of pharmacological effect. EC50 (concentration of terazosin that induces an effect at 50% of E max values) values were similar for systolic (29.9 ± 4.3 μg/L) and diastolic (28.7 ± 4.0 μg/L) blood pressure. A decrease in diastolic blood pressure was the most sensitive response after oral administration of a single dose of terazosin. Conclusion: The direct haemodynamic effects of terazosin can be characterized by an Emax effect compartment model.