Computational modeling to predict effect of treatment schedule on drug delivery to prostate in humans.
Computational modeling to predict effect of treatment schedule on drug delivery to prostate in humans.
复制标题
预测治疗方案对人类前列腺药物输送影响的计算模型。
DOI：
10.1158/1078-0432.ccr-06-1610
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Wientjes,MGuillaume
中科院分区：
文献类型：
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作者：
Hu,Leijun;Au,JessieL-S;Wientjes,MGuillaume
目的：为了评估一种计算方法，将实验数据在临床前models.Experimental Design描述阿霉素人体组织potential. Beagle犬阿霉素静脉推注，4小时输注，或96小时输注2毫克/公斤。测定血浆、前列腺（靶组织）、心脏（毒性）和主要组织中的浓度并建模。推注后获得模型参数，并基于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规模的人前列腺和heart.Results：在协议内vitroresults，组织最好的模型与两个隔间，一个快速和一个缓慢的平衡阿霉素配置文件。所开发的组织分布模型预测了所有三种给药方案的浓度，平均偏差为34%（中位数，29%）。对人类的种间放大研究表明，从推注到缓慢96小时输注的变化（a）对心脏和前列腺中的药物分配和蓄积有不同的影响，（B）使血浆中的峰浓度降低了100倍，但对最大心脏浓度的影响相对较小（降低了33%）。在人前列腺中的模拟药物暴露高于抑制肿瘤增殖所需的暴露，但低于30至50倍，需要为celldeath.Conclusion：本研究显示了一个基于计算的范例translatingin vitroandin vivoprecalinary数据和估计和比较不同的治疗方案后，在靶组织中的药物递送和药代动力学。
Purpose:To evaluate a computational approach that incorporates experimental data in preclinical models to depict doxorubicin human tissue pharmacokinetics.Experimental Design: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.Results:In agreement within vitroresults, 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 ∼100-fold but had relatively little effect on maximal heart concentration (∼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.Conclusion:The present study shows a computation-based paradigm for translatingin vitroandin vivopreclinical data and to estimate and compare the drug delivery and pharmacokinetics in target tissues after different treatment schedules.