Comparison of manual versus ambulatory blood pressure measurements with pharmacokinetic‐pharmacodynamic modeling of antihypertensive compounds: Application to moxonidine

Objectives To compare the results of the pharmacokinetic‐pharmacodynamic analyses of 24‐hour ambulatory blood pressure measurements and manual blood pressure data in patients receiving moxonidine. Methods 32 patients with borderline to mild‐to‐moderate hypertension were enrolled in a double‐blind, placebo‐controlled phase II study. After receiving placebo for 1 week (run‐in phase), the patients were randomly allocated to the placebo or the 0.6‐, 0.9‐, or 1.2‐mg dose groups. Placebo and moxonidine were administered once daily for 1 week (drug‐treatment phase). Four 24‐hour ambulatory blood pressure measurement profiles were obtained for each individual. Plasma samples (n = 9) and four measurements of manual blood pressure were taken at the start and end of the drug‐treatment phase. Two additional manual blood pressure measurements were taken during the run‐in and drug‐treatment phases. Results Pharmacokinetics was described by a one‐compartment model. For the 24‐hour ambulatory blood pressure measurements, baseline circadian patterns were described with a two‐cosine function model that included interindividual and interoccasion variability. Pharmacodynamics was described with use of an effect‐compartment model [ke0 = 0.37 (1/h)] and an Emax model. For diastolic blood pressure the maximum drug‐induced decrease (Emax) was 30.9 mm Hg and the steady‐state plasma drug concentration eliciting half of maximum effect (C50) was 1.33 μg/L. Interindividual variability was estimated for ke0 (24.8%) and Emax (33.3%). For the manual blood pressure measurements, data was described by a time‐invariant baseline model combined with an effect‐compartment model and an Emax model. Mean population estimates were in agreement with those obtained during the analysis of 24‐hour ambulatory blood pressure measurements. However, interindividual variability could be estimated for the baseline parameter only. Conclusions Although similar typical population estimates for the drug action–related parameters were obtained with use of manual blood pressure data and 24‐hour ambulatory blood pressure measurements, the latter allowed for a more detailed description of the individual pharmacodynamic profiles because interindividual variability in pharmacodynamic parameters could be estimated together with increased precision in parameter estimates. Clinical Pharmacology & Therapeutics (2000) 68, 18–27; doi: 10.1067/mcp.2000.106907