Girard P, Saumet J L, Dubois F, Boissel J P
INSERM, Lyon, France.
Eur J Clin Pharmacol. 1993;44(2):177-82. doi: 10.1007/BF00315477.
The concentration-effect relationships of pinacidil, a peripheral vasodilator, have been measured in 12 healthy adults who received placebo or pinacidil 25 mg daily for 1 week in a cross-over experiment. Diastolic blood pressure (DBP) and heart rate (HR) were recorded and blood samples were taken on days 1 and 7. Plasma drug concentration-time data were fitted by a biexponential function with zero-order input. The pharmacokinetic model was incorporated into a combined pharmacokinetic-dynamic model (PK-PD) using the Hill equation, which has three parameters: n, the sigmoidicity parameter, Emax the maximum effect and EC50 the concentration which gives 50% of Emax. For delta DBP, the parameter medians were estimated as n = 5, EC50 = 44.6 ng.ml-1 and Emax = 13.5 mmHg. A hysteresis loop was found when delta HR was plotted against concentration, which could be fitted by a linear effect compartment model. Simulations showed that experimental delta DBP points on Day 7 could be predicted from a simulated curve computed by the model using parameters estimated on Day 1. Using the simulation, it was possible to suggest an optimal dosage regimen for pinacidil tablets.
在一项交叉试验中，对12名健康成年人进行了外周血管扩张剂吡那地尔的浓度-效应关系测定，这些受试者接受了安慰剂或每日25毫克吡那地尔治疗，为期1周。记录了舒张压（DBP）和心率（HR），并在第1天和第7天采集了血样。血浆药物浓度-时间数据采用零级输入的双指数函数拟合。使用希尔方程将药代动力学模型纳入药代动力学-动力学联合模型（PK-PD），该方程有三个参数：n，S形参数；Emax，最大效应；EC50，产生50%Emax的浓度。对于ΔDBP，参数中位数估计为n = 5，EC50 = 44.6 ng.ml-1，Emax = 13.5 mmHg。当绘制ΔHR与浓度的关系图时发现了一个滞后环，可用线性效应室模型拟合。模拟结果表明，第7天的实验性ΔDBP点可以根据使用第1天估计的参数由模型计算出的模拟曲线进行预测。通过模拟，可以为吡那地尔片剂提出最佳给药方案。
