应用全身体生理药代动力学模型模拟健康成年人和肾功能受损患者比索洛尔的药代动力学。
Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling.
机构信息
Center for Drug Clinical Research, Shanghai University of Chinese Medicine, China.
出版信息
Acta Pharmacol Sin. 2012 Nov;33(11):1359-71. doi: 10.1038/aps.2012.103. Epub 2012 Oct 22.
AIM
To develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK) model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment.
METHODS
Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments. Based the tissue composition equations and drug-specific properties such as log P, permeability, and plasma protein binding published in literatures, the absorption and whole-body distribution of bisoprolol was predicted using the 'Advanced Compartmental Absorption Transit' (ACAT) model and the whole-body disposition model, respectively. Renal and hepatic clearances were simulated using empirical scaling methods followed by incorporation into the WB-PBPK model. Model refinements were conducted after a comparison of the simulated concentration-time profiles and pharmacokinetic parameters with the observed data in healthy adults following intravenous and oral administration. Finally, the WB-PBPK model coupled with a Monte Carlo simulation was employed to predict the mean and variability of bisoprolol pharmacokinetics in virtual healthy subjects and patients.
RESULTS
The simulated and observed data after both intravenous and oral dosing showed good agreement for all of the dose levels in the reported normal adult population groups. The predicted pharmacokinetic parameters (AUC, C(max), and T(max)) were reasonably consistent (<1.3-fold error) with the observed values after single oral administration of doses ranging from of 5 to 20 mg using the refined WB-PBPK model. The simulated plasma profiles after multiple oral administration of bisoprolol in healthy adults and patient with renal impairment matched well with the observed profiles.
CONCLUSION
The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in diverse normal adult human populations and patients with renal insufficiency.
目的
开发并评估比索洛尔的全身生理药代动力学（WB-PBPK）模型，并模拟其在健康成年人和肾功能损害患者中的暴露和处置。
方法
通过灌注受限隔室描述比索洛尔在 14 个组织隔室中的分布。根据文献中公布的组织组成方程和药物特有特性（如 log P、渗透性和血浆蛋白结合），使用“高级隔室吸收传递”（ACAT）模型和全身分布模型分别预测比索洛尔的吸收和全身分布。通过经验比例法模拟肾清除率和肝清除率，然后将其纳入 WB-PBPK 模型。在比较静脉注射和口服给药后健康成年人的模拟浓度-时间曲线和药代动力学参数与观察数据后，进行模型改进。最后，使用 WB-PBPK 模型结合蒙特卡罗模拟来预测虚拟健康受试者和患者中比索洛尔的药代动力学的均值和变异性。
结果
静脉注射和口服给药后，报告的正常成年人群体的所有剂量水平的模拟和观察数据均吻合良好。使用经改进的 WB-PBPK 模型，预测的药代动力学参数（AUC、C(max)和 T(max)）与观察到的 5 至 20 mg 单剂量口服后的值相当一致（<1.3 倍误差）。健康成年人和肾功能损害患者多次口服比索洛尔后的模拟血浆曲线与观察到的曲线吻合良好。
结论
WB-PBPK 模型成功预测了不同正常成年人群体和肾功能不全患者中比索洛尔的静脉内和口服药代动力学，涵盖了多个剂量水平。
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