Predicting the effects of 8C2, a monoclonal anti-topotecan antibody, on plasma and tissue disposition of topotecan.
Predicting the effects of 8C2, a monoclonal anti-topotecan antibody, on plasma and tissue disposition of topotecan.
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DOI：
10.1007/s10928-013-9346-9
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发表时间：
2014-02
影响因子：
2.5
通讯作者：
Balthasar JP
中科院分区：
文献类型：
--
作者：
Shah DK;Balthasar JP
我们正在研究一种反向靶向策略，以减少拓扑替康（一种模型化疗药物）腹腔内（IP）给药引起的剂量限制性全身毒性。该方法利用抗拓扑替康抗体的全身性共施用来改变拓扑替康的血浆和组织处置动力学。为了更好地预测高亲和力抗拓扑替康单克隆抗体8C2对拓扑替康药代动力学的影响，建立了两个数学模型并进行了评价。模型1是一种基于生理学的混合药代动力学（PBPK）模型，通过合并托泊替康的PBPK模型与8C2药代动力学的简单两室模型创建。模型2是通过将IgG的PBPK模型与拓扑替康的PBPK模型合并而开发的综合PBPK模型。为了帮助验证来自两个模型的模拟结果，进行了组织分布实验，其中在小鼠中共同施用托泊替康和8C2。通过计算所有组织的中位数百分比预测误差（%PE）比较实验和模拟数据。对于两种模型，所有组织的中位%PE值均小于100%，表明预测值平均小于血浆和组织拓扑替康浓度实测值的2倍。一般而言，发现模型2比模型1更能预测数据集，因为模型2的总体中位%PE值（%PE=63）小于模型1（%PE=73）。
We are investigating an inverse targeting strategy to reduce the dose limiting systemic toxicities resultant from intraperitoneal (IP) administration of topotecan, a model chemotherapeutic drug. This approach utilizes systemic co-administration of anti-topotecan antibodies to alter the plasma and tissue disposition kinetics of topotecan. To better predict the effects of 8C2, a high affinity anti-topotecan monoclonal antibody, on the pharmacokinetics of topotecan, two mathematical models have been developed and evaluated. Model 1 is a hybrid physiologically based pharmacokinetic (PBPK) model that was created by merging a PBPK model for topotecan with a simple two compartment model of 8C2 pharmacokinetics. Model 2 is a comprehensive PBPK model developed by merging a PBPK model for IgG with a PBPK model for topotecan. To help validate the simulation results from both the models, a tissue distribution experiment was conducted, in which topotecan and 8C2 were co-administered in mice. Experimental and simulated data were compared by calculating the median percent prediction error (%PE) for all tissues. For both models, the median %PE values for all the tissues were less than 100%, indicating that the predicted values were, on average, less than two-fold the observed plasma and tissue topotecan concentrations values. In general model 2 was found to be more predictive of the data set than model 1, as the overall median %PE value for model 2 (%PE=63) was less than model 1 (%PE=73).
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影响因子：
3.8
作者：
Lobo, ED;Soda, DM;Balthasar, JP
通讯作者：
Balthasar, JP
影响因子：
5
作者：
PUTTERMAN, C;BENCHETRIT, E;LEVY, M
通讯作者：
LEVY, M
DOI：
10.1007/bf01062191
发表时间：
1991-02-01
期刊：
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS
影响因子：
--
作者：
BERNAREGGI, A;ROWLAND, M
通讯作者：
ROWLAND, M
影响因子：
2.5
作者：
Mager, DE;Jusko, WJ
通讯作者：
Jusko, WJ
DOI：
10.1016/j.jchromb.2004.11.035
发表时间：
2005-02-25
影响因子：
3
作者：
Chen, J;Balthasar, JP
通讯作者：
Balthasar, JP