厄贝沙坦在健康志愿者体内的药代动力学-药效学结合模型

Pharmacokinetic-pharmacodynamic modeling of irbesartan in healthy Chinese adult volunteers

目的研究厄贝沙坦在健康志愿者体内的药代动力学-药效学结合模型,探讨其临床药效学特征。方法18例健康志愿者厄贝沙坦片口服给药,测定血药浓度,同时测量收缩压(SBP)、舒张压(DBP)及心率(HR)等药效指标。计算厄贝沙坦的药动学参数,并根据sheiner效应室模型理论,计算药效学参数。结果厄贝沙坦的血药浓度时间曲线呈二室模型;厄贝沙坦抑制SBP和DBP的效应滞后于血药浓度,药效与血药浓度之间存在逆时针滞后环,药效和效应室浓度的关系符合SigmoidEmax模型。厄贝沙坦抑制SBP和DBP的药效学参数Emax分别为(14.8±1.5)和(9.8±2.1)mmHg,EC50分别为(0.29±0.11)和(0.18±0.07)mg·L-1,Keo分别为(0.62±0.09)和(0.68±0.07)h-1。结论建立了厄贝沙坦在健康者体内的药代动力学-药效学结合模型,有利于临床合理用药。

Aim To investigate the combined pharmacokinetic-pharmacodynamic(PK-PD) model of irbesartan in healthy Chinese male volunteers. Methods Eighteen healthy male volunteers received 300 mg irbesartan tablet orally. The plasma drug concentration (C_p) was determined by HPLC and pharmacologic effects, including SBP, DBP and HR, were measured simultaneously. The pharmakinetic and PK-PD model parameters were calculated. Results The pharmacokinetic profiles were best fitted a two-compartment open model. There was a hysteresis loop between effects and plasma concentrations. The relationship between effects and effect compartment concentrations of drugs could be represented by the Sigmoid-E_ max model. Conclusion We successfully eatablished the PK-PD model of irbesartan in healthy male volunteers. These findings may provide a more rational basis for patient-specific dosage individualization.