Population pharmacokinetic-pharmacodynamic modeling of moxonidine using 24-hour ambulatory blood pressure measurements.
OBJECTIVE
To develop a model for 24-hour ambulatory blood pressure measurements (ABPM) that can be applied in a pharmacokinetic-pharmacodynamic model.


METHODS
Four different data sets were prepared from 2 studies to accommodate different modeling strategies. In study A, a double-blind placebo-controlled study in 47 patients, 24-hour ABPM profiles (74 to 99 measurements per profile) were obtained during the placebo run-in phase and after 3, 5, and 11 weeks during the treatment. Three to 5 plasma samples were taken. Cosine and polynomial models were evaluated to describe the circadian rhythm in blood pressure based on 3 data sets (1: only run-in data; 2: only placebo data; 3: all data). In study B, a double-blind placebo-controlled study in 94 patients, two 24-hour ABPM profiles per patient (during placebo run-in and after 8 weeks) were recorded and randomly reduced to 15 measurements per profile to evaluate the robustness of the baseline model.


RESULTS
The mean moxonidine clearance was 35 L/h, and the volume of distribution was 132 L. The final baseline model consisted of 2 cosine terms with fixed-effect parameters for rhythm-adjusted 24-hour mean blood pressure, amplitude, phase, and period; random-effect parameters for interindividual variability in rhythm-adjusted 24-hour mean, amplitude, and clock time; and interoccasion variability in rhythm-adjusted 24-hour mean and clock time. The final baseline model was combined with an Emax model for the drug effect. An effect compartment was used (kco = 0.198 h-1). The maximum decrease in diastolic blood pressure (Emax) was 16.7%, and EC50 was 0.945 microgram/L.


CONCLUSIONS
The pharmacokinetic-pharmacodynamic model for 24-hour ABPM can be used to estimate the concentration-effect relationship of antihypertensive drugs.
Hempel
G
G
Eli Lilly and Company Limited, Department of Clinical Pharmacology, Windlesham, Surrey, United Kingdom.
Karlsson
M O
MO
de Alwis
D P
DP
Toublanc
N
N
McNay
J
J
Schaefer
H G
HG
D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D018660:Blood Pressure Monitoring, Ambulatory; D002940:Circadian Rhythm; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D007093:Imidazoles; C043482:moxonidine