卡维地洛人体药动学与药效学结合模型研究

采用间接药效学模型和效应室模型两种药效学模型分别进行卡维地洛药动学与药效学关系研究, 比较两种药效学模型的拟合程度。高效液相色谱法 (荧光) 测定20名健康志愿者单次口服20 mg卡维地洛片后卡维地洛经时血药浓度, 以DAS 2.0实用药动学计算程序计算卡维地洛药动学参数。同时测定给药前后动脉收缩压和舒张压, 计算降压效果。卡维地洛片主要药动学参数t_1/2为 (4.56 ± 2.56) h, C_max为 (46.29 ± 21.07) ng·mL^-1, AUC_0-∞为 (173.76 ± 87.36) ng·mL^-1·h。间接药效模型主要参数K_in为 (0.41 ± 0.31) % h^-1, K_out为 (0.40 ± 0.26) h^-1, IC₅₀为 (24.40 ± 21.10) ng·mL^-1, AUE为 (3.82 ± 1.46) % h。效应室模型主要参数K_e0为 (0.35 ± 0.27) h^-1, EC₅₀为 (24.30 ± 24.30) ng·mL^-1, AUE为 (5.65 ± 2.54) % h。该方法可用于卡维地洛片人体药动学研究。由AIC值可知, 效应室模型可更好的应用于卡维地洛药动学-药效学结合研究。

Comparison of different pharmacodynamic models for pharmacokinetic-pharmacodynamic (PK-PD) modeling of carvedilol

The paper is aimed to investigate the pharmacokinetic (PK) and the pharmacodynamic (PD)  properties of carvedilol using indirect response and effect-compartment link models, and compare the fitness of PK-PD models.  Twenty male healthy Chinese volunteers received a single oral dose of 20 mg of carvedilol.  The plasma concentrations of carvedilol were determined by reversed-phase HPLC method with fluorescence detection, and the pharmacokinetic parameters were calculated by DAS2.0.  The mean arterial blood pressure was measured and the pharmacodynamics of carvedilol was characterized by tail-cuff manometry.  The main pharmacokinetic parameters of carvedilol were as follows, t_1/2 (4.56 ± 2.56) h, C_max (46.29 ± 21.07) ng·mL^-1, AUC_0-∞ (173.76 ± 87.36) ng·mL^-1·h.  The estimated K_in was (0.41 ± 0.31) % h^-1, K_out was (0.40 ± 0.26) h^-1, the IC₅₀ value was (24.40 ± 21.10) ng·mL^-1 and the area under the effect curve (AUE) was (3.82 ± 1.46) % h for the indirect response PD model.  The K_e0 was (0.35 ± 0.27) h^-1, the EC₅₀ was (24.30 ± 24.30) ng·mL^-1, and the AUE was (5.65 ± 2.54) % h for the effect-compartment model.  The HPLC method can be used for the pharmacokinetic study of carvedilol.  The proposed effect-compartment link model provided more appropriate and better-fitting PK/PD characteristics than the indirect response model in Chinese healthy volunteers according to Akaike’s   information criterion values.