Variability in response to antihypertensive drug therapy: From population based therapy towards individualized treatment

Variability in blood pressure (BP) and variability in antihypertensive drug response is a multifaceted phenomenon. Physicians and researchers face the challenge to recognize this variation for correct initiation and evaluation of antihypertensive therapy. In this thesis pharmacokinetic and pharmacodynamic modeling was used with the aim to evaluate and quantify the variability in BP and BP response between patients. Furthermore, suggestions are provided for new strategies to individualize the drug treatment of hypertension. Data used in this thesis are derived from the SUNSET (Surinamese in the Netherlands: study on health and ethnicity) and ROTATE studies. In the ROTATE study (open-label, crossover) patients were rotated for antihypertensive treatment with a single drug from 5 drug classes. Application of the population approach, using nonlinear mixed effects modeling (NONMEM), showed that this methodology is suitable to quantify the average parameters that describe the 24-hour SBP profile as well as the amount of variability between patients in these parameters. Ethnicity was found to explain a significant part of differences between patients. Also, it was possible to identify a concentration-effect relationship for the antihypertensive drug eprosartan in hypertensive patients including quantification of the between-patient variability in this relationship. Creole Surinamese exhibit no drug response in contrast to white Dutch and Hindustani Surinamese. Genetic factors did not explain enough variation in BP and in the effect of BP lowering drugs to be clinically useful so far. For future research, the developed pharmacokinetic-pharmacodynamic models may be used to reduce the measurement frequency for assessment of the diurnal SBP profile and to individualize antihypertensive drug therapy.