Population Pharmacokinetic-Pharmacodynamic Modeling of Captopril in Healthy Volunteers

건강한 자원자에서 Captopril의 집단 약동/약력학적 모델 연구

Background : Captopril, the first orally active inhibitor of the angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. A model for 24-hour blood pressure considering diurnal variation was expected to be an approach for better understanding of plasma concentration -plasma angiotensin converting enzyme (ACE) activity- hypotensive effect relationships. Methods : Data were obtained from a randomized, single blind, and crossover study in healthy subjects. As a first modeling step, a model for 24-hour ambulatory blood pressure measurement(ABPM) was developed from 12 subjects receiving placebo, then this placebo model was used in a final PK/PD model from 12 subjects receiving captopril 50 mg. A nonlinear mixed-effects model incorporating time gap(hysteresis) between PK and PD steps was applied. Model building was evaluated using the goodness-of-fit criteria and the change in MOFV(minimum objective function value). Results : The time course of drug concentrations was best explained with a first order absorption and elimination one compartment open linear model. The ABPM data was best discribed by a model, which consisted of 2 cosine functions for diurnal fluctuation and a Hill's model using effect compartment for drug effect. Plasma captopril concentrations, plasma ACE activities, and diastolic blood pressures(DBP) were fitted simultaneously $(R^2=0.9357,\;0.9685,\;and\;0.5966,\;respectively)$. The estimated population mean value of clearance(CL/F) and the mean volume of distribution(Vd/F) were 54.2 L/hr(8.6 SE %) and 38.5 L(9.1 SE %), respectively. The plasma ACE activity at steady $state(ACE_{ss})$ and mean DBP were 37.0 U/L(7.6 SE %) and 69.3 mmHg(2.3 SE %), respectively. The maximum predicted fall in DBP was 13.5%(17.5 SE %) from the baseline. Inhibition of ACE activity resulting in 50% maximum hypotensive $effect(ACEI_{50})$ was 48.2% (7.8 SE %). Conclusion : The time course of BP changes in each individual subject could be well characterized by this model. This population pharmacokinetic-pharmacodynamic modeling of captopril can be used in determining the optimal regimen or evaluation of new drugs.