Pharmacokinetic–Pharmacodynamic Modeling of the Antihypertensive Effect of Eprosartan in Black and White Hypertensive Patients

Abstract

It is well recognized that many antihypertensive drugs exhibit large interindividual variability in effect and that this wide range of patient response to antihypertensive drugs is a major problem in achieving blood pressure (BP) control. Variability in both drug concentration and drug effect may cause the heterogeneity in antihypertensive drug response. However, for most antihypertensive drugs, no clear relationship between drug concentration and its effect on BP has been reported. This study aimed to describe the relationship between eprosartan exposure and its effect on the systolic blood pressure (SBP) using population pharmacokinetic-pharmacodynamic modeling. Interindividual variability in pharmacokinetics and pharmacodynamics was quantified and the influence of covariates on this relationship was evaluated. Eprosartan plasma concentrations and SBP measurements were determined in 86 mildly hypertensive patients from the ROTATE study aged 48.1±7.6years with different ethnic backgrounds (33 White Dutch, 41 Creole Surinamese, 12 Hindustani Surinamese). In 12 of these patients, pharmacokinetics were densely sampled and 24-h ambulatory BP measurements were obtained. Data were analyzed using nonlinear mixed effects modeling. Eprosartan concentration-time profiles were adequately described with a two-compartment pharmacokinetic model with zero-order absorption. A log-linear relationship was used to describe the relationship between concentration and the decrease in SBP. A hypothetical effect compartment was used to describe hysteresis in the drug effect. Approximately 80% of the maximum decrease in SBP was observed after 24days. Interindividual variability in drug response was 65% and decreased to 14% when ethnicity was added as covariate. Creole Surinamese exhibited no drug response in contrast to White Dutch and Hindustani Surinamese [-2.6mmHg per (ng/ml)]. The developed pharmacokinetic-pharmacodynamic model allows the quantification and explanation of variability in SBP between individuals with ethnicity as a useful determinant of responsiveness to eprosartan.