Application of pharmacokinetic-pharmacodynamic modeling to predict the kinetic and dynamic effects of anti--methotrexate antibodies in mice
Application of pharmacokinetic-pharmacodynamic modeling to predict the kinetic and dynamic effects of anti--methotrexate antibodies in mice
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DOI：
10.1002/jps.10432
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发表时间：
2003-08-01
影响因子：
3.8
通讯作者：
Balthasar, JP
中科院分区：
文献类型：
--
作者：
Lobo, ED;Soda, DM;Balthasar, JP
我们已经表明，静脉内（iv）施用抗甲氨蝶呤（MTX）抗体（AMAb）减少腹膜内（ip）MTX疗法的全身暴露，并且我们已经提出AMAb对MTX全身暴露的作用将允许减少MTX诱导的全身毒性（即，产生期望的拮抗作用）。然而，许多文献报道表明，抗毒素抗体偶尔会表现出意想不到的激动剂样活性，增加其配体诱导的毒性程度。在本报告中，我们利用药代动力学-药效学（PKPD）模型预测AMAb增加或减少MTX诱导的小鼠体重减轻幅度的潜力。模拟预测，抗MTX免疫球蛋白G（AMI）和抗MTX Fab片段（AMF）将导致MTX毒性的增加或减少，其作用取决于所使用的给药方案。基于计算机模拟，选择两种方案用于预测的激动或拮抗作用的体内评价。小鼠单克隆AMI和AMF的生产，纯化，并进行了表征。激动作用后，24小时输注的ip MTX（10 mg/kg）和iv给药的等摩尔剂量的AMI。72小时后，ip MTX（5 mg/kg）和iv输注等摩尔剂量的AMF的拮抗作用进行了测试。与激动剂样活性的模型预测一致，24小时AMI方案导致显著增加的动物死亡率（所有动物死亡，p < 0.005）和平均最低体重减轻（p < 0.005）。同样与PKPD模型的预测一致，72小时AMF方案显著降低动物死亡率和平均最低体重减轻（p < 0.01）。因此，这些研究表明，可以通过使用综合PKPD模型来预测抗毒素抗体的激动和拮抗作用。(C)2003 Wiley-Liss，Inc.和美国药剂师协会
We have shown that intravenous (iv) administration of anti-methotrexate (MTX) antibodies (AMAb) reduces the systemic exposure of intraperitoneal (ip) MTX therapy, and we have proposed that AMAb effects on MTX systemic exposure would allow a reduction in MTX-induced systemic toxicity (i.e., producing a desirable antagonistic effect). However, many literature reports have shown that anti-toxin antibodies occasionally demonstrate unexpected agonist-like activity, increasing the extent of toxicity induced by their ligand. In this report, we have utilized a pharmacokinetic-pharmacodynamic (PKPD) model to predict the potential of AMAb to increase or decrease the magnitude of MTX-induced body weight loss in mice. Simulations predicted that both anti-MTX immunoglobulin G (AMI) and anti-MTX Fab fragments (AMF) would lead to increases or decreases in MTX toxicity, with effects dependent on the dosing protocol used. Based on the computer simulations, two protocols were selected for in vivo evaluation of predicted agonistic or antagonistic effects. Murine monoclonal AMI and AMF were produced, purified, and characterized. Agonistic effects were tested after 24-h infusion of ip MTX (10 mg/kg) and iv administration of an equimolar dose of AMI. Antagonistic effects were tested after 72-h infusion of ip MTX (5 mg/kg) and iv infusion of an equimolar dose of AMF. Consistent with model predictions of agonist-like activity, the 24-h AMI protocol led to significantly increased animal mortality (all animals died, p < 0.005) and mean nadir weight loss (p < 0.005). Also consistent with the predictions of the PKPD model, the 72-h AMF protocol significantly decreased animal mortality and mean nadir body weight loss (p < 0.01). Thus, these studies demonstrate that agonistic and antagonistic effects of anti-toxin antibodies may be predicted through the use of an integrated PKPD model. (C) 2003 Wiley-Liss, Inc. and the American Pharmacists Association.