A mathematical model of a recombinant humanized anti-cocaine monoclonal antibody's effects on cocaine pharmacokinetics in mice.
A mathematical model of a recombinant humanized anti-cocaine monoclonal antibody's effects on cocaine pharmacokinetics in mice.
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DOI：
10.1016/j.lfs.2017.07.006
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发表时间：
2017-09-01
期刊：
影响因子：
6.1
通讯作者：
Norman AB
中科院分区：
文献类型：
--
作者：
Wetzel HN;Zhang T;Norman AB
重组人源化抗可卡因单克隆抗体（mAb）h2 E2作为可卡因滥用的免疫疗法正处于临床前开发的高级阶段。假设h2 E2结合并隔离血液中的可卡因。建立了h_2E_2对可卡因分布影响的三室模型。该模型假设h2 E2与可卡因结合，并且h2 E2-可卡因复合物不进入大脑，而是分布在中枢和外周隔室之间。游离可卡因从中央和外周室消除，并且h2 E2和h2 E2-可卡因复合物仅从中央室消除。该模型针对一个新的数据集进行了测试，该数据集测量了在存在和不存在h2 E2的情况下一小时内大脑和血浆中的可卡因浓度。mAb显著增加血浆可卡因浓度，同时脑浓度显著降低。两组的血浆浓度在1小时采样期内均下降。通过合理生理范围内的一组参数，三室模型能够定性和定量地模拟抗体存在下血浆浓度的增加和抗体存在下脑峰浓度的降低。重要的是，该模型将血浆浓度随时间的下降解释为可卡因-h2 E2复合物分布到外周室中。该模型将有助于靶向理想的mAb PK/PD特性，从而加速先导候选抗药物mAb的鉴定。
A recombinant humanized anti-cocaine monoclonal antibody (mAb), h2E2, is at an advanced stage of pre-clinical development as an immunotherapy for cocaine abuse. It is hypothesized that h2E2 binds to and sequesters cocaine in the blood. A three-compartment model of the effects of h2E2 on cocaine's distribution was constructed. The model assumes that h2E2 binds to cocaine and that the h2E2-cocaine complex does not enter the brain but distributes between the central and peripheral compartments. Free cocaine is eliminated from both the central and peripheral compartments, and h2E2 and the h2E2-cocaine complex are eliminated from the central compartment only. This model was tested against a new dataset measuring cocaine concentrations in the brain and plasma over one hour in the presence and absence of h2E2. The mAb significantly increased plasma cocaine concentrations with a concomitant significant decrease in brain concentration. Plasma concentrations declined over the 1-hour sampling period in both groups. With a set of parameters within reasonable physiological ranges, the three-compartment model was able to qualitatively and quantitatively simulate the increased plasma concentration in the presence of the antibody and the decreased peak brain concentration in the presence of antibody. Importantly, the model explained the decline in plasma concentrations over time as distribution of the cocaine-h2E2 complex into a peripheral compartment. This model will facilitate the targeting of ideal mAb PK/PD properties thus accelerating the identification of lead candidate anti-drug mAbs.
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影响因子：
5.3
作者：
Stevens MW;Henry RL;Owens SM;Schutz R;Gentry WB
通讯作者：
Gentry WB
影响因子：
4.8
作者：
Kirley TL;Norman AB
通讯作者：
Norman AB
影响因子：
7.3
作者：
Paula, S;Tabet, MR;Ball, WJ
通讯作者：
Ball, WJ
DOI：
10.1016/j.bbrc.2017.04.117
发表时间：
2017-06-03
影响因子：
3.1
作者：
Wetzel HN;Webster RP;Saeed FO;Kirley TL;Ball WJ;Norman AB
通讯作者：
Norman AB
DOI：
10.1124/jpet.106.111781
发表时间：
2007-01-01
影响因子：
3.5
作者：
Norman, Andrew B.;Tabet, Michael R.;Ball, William J.
通讯作者：
Ball, William J.