PHARMACOKINETICS AND PHARMACODYNAMICS OF CANDESARTAN AFTER ADMINISTRATION OF ITS PRO-DRUG CANDESARTAN CILEXETIL IN PATIENTS WITH MILD-TO-MODERATE ESSENTIAL-HYPERTENSION - A POPULATION ANALYSIS

Objective: The pharmacokinetics and pharma codynamics of the angiotens in (AT) II receptoz, AT1-subtype, antagonist candesartan were investig ated in a dose-finding study in 232 patients of either gender, aged 28 -69 years and weighing 54-110 kg. The study was a double-blind, placeb o-controlled trial in which oral doses of 2, 4, 8, 12 and 16 mg once d aily were given as the pro-drug candesartan cilexetil from day 0 to da y 28. Results: The population pharmacokinetics of candesartan could be best described by a two-compartment body model, parameterized in term s of clearance (14.1 1.h(-1)), central volume of distribution (118 1), peripheral volume (272 1) and intercompartmental clearance (15.41.h(- 1)). From these model parameters, a cumulation half-life (t(1/2,beta)) of 29 h was derived. Age and weight were influencing factors for the distribution and elimination of the drug. Systolic and diastolic blood pressure were lowered by the treatment in a dose-dependent fashion. T he maximum effect of each dose was reached after repeated administrati on. The link between plasma concentrations and effect could be describ ed by a linear model when trough concentrations and blood pressure, me asured at the same time, were modelled. In this model, the time depend ence is implicitly handled as the trough concentrations increased duri ng repeated administration. After treatment with the highest dose used in the trial (16 mg), the population estimate for the diastolic blood pressure was reduced from 103.2 mmHg (pre-dose day 0) to 93.3 mmHg (o n day 29) and the systolic blood pressure from 154.6 mmHg (pre-dose da y 0) to 137.9 mmHg (on day 29). None of the covariates (age, weight, g ender) had an influence on the concentration-effect relationship.