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 a nalyses 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 receiv ing 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 moxon idine were administered once daily for 1 week (drug-treatment phase). Pour 24-hour ambulatory blood pressure measurement profiles were obtained for ea ch 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 pattern s were described with a two-cosine function model that included interindivi dual and interoccasion variability, Pharmacodynamics was described with use of an effect-compartment model [k(e)0 = 0.37 (1/h)] and an E-max model. Fo r diastolic blood pressure the maximum drug-induced decrease (E-max) was 30 .9 mm Hg and the steady-state plasma drug concentration eliciting half of m aximum effect (C-50) was 1.33 mu g/L. Interindividual variability was estim ated for k(e0) (24.8%) and E-max (33.3%). For the manual blood pressure mea surements, data was described by a time-invariant baseline model combined w ith an effect-compartment model and an E-max,, model. Mean population estim ates were in agreement with those obtained during the analysis of 24-hour a mbulatory blood pressure measurements. However, interindividual variability could be estimated for the baseline parameter only. Conclusions: Although similar typical population estimates for the drug act ion-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 bec ause interindividual variability in pharmacodynamic parameters could be est imated together with increased precision in parameter estimates.