Comparison of manual versus ambulatory blood pressure measurements with pharmacokinetic-pharmacodynamic modeling of antihypertensive compounds: application to moxonidine.
OBJECTIVE
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.
Trocóniz
I F
IF
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona.
de Alwis
D P
DP
Tillmann
C
C
Callies
S
S
Mitchell
M
M
Schaefer
H G
HG
D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001795:Blood Pressure Determination / Q000295:instrumentation / Q000379:methods*; D018660:Blood Pressure Monitoring, Ambulatory; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D012720:Severity of Illness Index; D013997:Time Factors
D000959:Antihypertensive Agents; D007093:Imidazoles; C043482:moxonidine