Pharmacodynamics of controlled release verapamil in patients with hypertension: an analysis using spline functions

Biopharmaceutics & Drug Disposition
Leon AaronsSuneel Gupta

Abstract

To use a nonparametric approach involving longitudinal splines to model the baseline blood pressure profile and investigate the impact of this modelling on the pharmacodynamic analysis for verapamil in patients with angina or hypertension. Dose ranging studies were conducted in patients with hypertension and with angina. Subjects received doses of 120, 180, 360 or 540 mg racemic verapamil. Pharmacodynamic data were created by subtracting the (systolic) blood pressure following active drug from the placebo response, either by direct subtraction or after modelling the baseline with a longitudinal spline model fitted to the placebo data by nonlinear mixed effects modelling. An Emax model was then used to describe the relationship between change in blood pressure and (R-)verapamil plasma concentration. The maximum decrease in systolic blood pressure was found to be 57.6 (+/- 26.1) mm and the C50 was 420 (+/- 349) microg/l for the data obtained by direct subtraction of the placebo data. Similar results were obtained when a cubic spline model was used to describe each individual's placebo response. However, the use of a population spline model only allowed a linear pharmacodynamic model to be fitted to the resulting data. Sparse data...Continue Reading

Citations

May 1, 2008·Journal of Pharmacokinetics and Pharmacodynamics·Chantaratsamon DansirikulMats O Karlsson
Apr 30, 2008·Journal of Pharmacological and Toxicological Methods·Facundo M BerteraChristian Höcht
Nov 12, 2005·Journal of Animal Science·K R RobbinsJ K Bertrand

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