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Pharmacokinetics of controlled‐release verapamil in healthy volunteers and patients with hypertension or angina
Author(s) -
Gupta Suneel,
Modi Nishit B.,
Sathyan Gayatri,
Ho Pailing,
Aarons Leon
Publication year - 2002
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.289
Subject(s) - verapamil , pharmacokinetics , medicine , population , pharmacodynamics , pharmacology , angina , calcium , environmental health , myocardial infarction
Aims: To study the dose‐ranging population pharmacokinetics of controlled release verapamil in healthy subjects and patients with angina or hypertension. To characterize the pharmacodynamics of controlled‐release verapamil in patients with hypertension. Methods: Dose‐ranging studies were conducted in healthy volunteers and patients with hypertension and angina. Subjects received doses of 120, 180, 360, or 540 mg racemic verapamil as an osmotic controlled‐release formulation. A population pharmacokinetic model involving zero‐order release of verapamil into the gastrointestinal tract with first‐order absorption and elimination was used to describe the steady‐state plasma concentration profile for R ‐ and S ‐verapamil. A population sigmoid E max pharmacodynamic model was used to describe the effect of R ‐ and S ‐verapamil on mean arterial blood pressure. Results: S ‐verapamil had an approximate 4‐fold greater apparent clearance than R ‐verapamil in both healthy volunteers and patients. The apparent plasma clearance of R ‐ and S ‐verapamil in healthy volunteers decreased over the dose range of 120–540 mg. A similar dose‐dependent decrease in apparent plasma clearance was also noted in patients. None of the patient demographic variables examined (age, total body weight, lean body weight, body mass index, and height) explained the variability in verapamil pharmacokinetics. The pharmacodynamic model describing the relationship between verapamil plasma concentration and mean arterial blood pressure indicated that the S ‐verapamil had a 3.6‐fold lower estimated EC 50 compared to R ‐verapamil. Conclusions: The results from this dose‐ranging pharmacokinetic investigation in healthy volunteers and patients are consistent with previous reports in healthy subjects. S ‐verapamil is cleared more rapidly than R ‐verapamil and the estimated EC 50 for S ‐verapamil was 3.6‐fold lower than for R ‐verapamil. Estimated EC 50 values for R ‐ and S ‐verapamil decreased with increasing age and decreasing weight. Copyright © 2002 John Wiley & Sons, Ltd.