Hu Leijun, Au Jessie L-S, Wientjes M Guillaume
College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
Clin Cancer Res. 2007 Feb 15;13(4):1278-87. doi: 10.1158/1078-0432.CCR-06-1610.
To evaluate a computational approach that incorporates experimental data in preclinical models to depict doxorubicin human tissue pharmacokinetics.
Beagle dogs were given 2 mg/kg doxorubicin as i.v. bolus, 4-h infusion, or 96-h infusion. Concentrations in plasma, prostate (target tissue), heart (toxicity), and major tissues for disposition were determined and modeled. Model parameters were obtained after the bolus injection with model validation based on the 4-h and 96-h infusion data. Clinical pharmacokinetic data and scale-up gave doxorubicin profiles in human prostate and heart.
In agreement with in vitro results, tissues were best modeled with two compartments, one rapidly and one slowly equilibrating. The developed tissue distribution model predicted concentrations for all three administration regimens well, with an average deviation of 34% (median, 29%). Interspecies scale-up to humans showed that the change from a bolus injection to a slow, 96-h infusion (a) had different effects on the drug partition and accumulation in heart and prostate, and (b) lowered the peak concentration in the plasma by approximately 100-fold but had relatively little effect on maximal heart concentration ( approximately 33% lower). The simulated drug exposure in a human prostate was above the exposure required to inhibit tumor proliferation but was 30 to 50 times below that needed for cell death.
The present study shows a computation-based paradigm for translating in vitro and in vivo preclinical data and to estimate and compare the drug delivery and pharmacokinetics in target tissues after different treatment schedules.
评估一种将实验数据纳入临床前模型以描述多柔比星人体组织药代动力学的计算方法。
给比格犬静脉推注、4小时输注或96小时输注2mg/kg多柔比星。测定并模拟血浆、前列腺（靶组织）、心脏（毒性）和主要处置组织中的浓度。在推注注射后获得模型参数，并根据4小时和96小时输注数据进行模型验证。临床药代动力学数据和放大处理得出了多柔比星在人体前列腺和心脏中的分布情况。
与体外结果一致，组织用两个隔室建模效果最佳，一个快速平衡，一个缓慢平衡。所开发的组织分布模型对所有三种给药方案的浓度预测良好，平均偏差为34%（中位数为29%）。种间放大至人体显示，从静脉推注改为缓慢的96小时输注（a）对药物在心脏和前列腺中的分配和蓄积有不同影响，（b）使血浆中的峰值浓度降低了约100倍，但对心脏最大浓度的影响相对较小（降低约33%）。模拟的人体前列腺中的药物暴露高于抑制肿瘤增殖所需的暴露，但比细胞死亡所需的暴露低30至50倍。
本研究展示了一种基于计算的范例，用于转化体外和体内临床前数据，并估计和比较不同治疗方案后靶组织中的药物递送和药代动力学。
