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  • Title: Comparison of manual versus ambulatory blood pressure measurements with pharmacokinetic-pharmacodynamic modeling of antihypertensive compounds: application to moxonidine.
    Author: Trocóniz IF, de Alwis DP, Tillmann C, Callies S, Mitchell M, Schaefer HG.
    Journal: Clin Pharmacol Ther; 2000 Jul; 68(1):18-27. PubMed ID: 10945312.
    Abstract:
    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 [k(e0) = 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 microg/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.
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