A pharmacodynamic model of the effects of controlled-onset extended-release verapamil on 24-hour ambulatory blood pressure

OBJECTIVE: To formulate and evaluate a pharmacodynamic model that characterizes the effects of S-verapamil on the circadian 24-hour ambulatory blood pressure (ABP). METHODS: ABP was recorded in 19 hypertensive patients off drug, and following administration of the targeted dose of COER-V given once daily for at least 30 days. Blood samples were collected after the last dose for determination of the pharmacokinetic of S-verapamil. ABP vs. time was analyzed using a cosinor function, and the effects of S-verapamil on ABP were fitted using the pharmacodynamic model. RESULTS: COER-V decreased average systolic and diastolic blood pressures (mesors): baseline, 142 +/- 10 and 90 +/- 7; treated, 132 +/- 8.8 and 83 +/- 6.6 mmHg, respectively (p < 0.001). COER-V had no effect on the amplitude, cycle or the time shift (acrophase). The mean +/- SD time to peak and maximal S-verapamil concentrations were 9.5 +/- 1.2 hours and 46.4 +/- 35.8 ng/ml, respectively. Model estimates of the maximal inhibited systolic (Emax S), diastolic. (Emax D) pressures and C50 were 101 +/- 14 mmHg, 61 +/- 9.9 mmHg and 32.9 +/- 22.8 ng/ml, respectively. The model fit of the data was satisfactory and parameter estimates were precise. CONCLUSIONS: The model may be useful to characterize the relationship between plasma concentrations of verapamil and the antihypertensive effects of the drug and may be suitable for characterizing the effect of drugs on biological functions displaying oscillatory behavior.