Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate
Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate
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DOI：
10.1111/j.1365-2125.2011.04084.x
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发表时间：
2012-02-01
影响因子：
3.4
通讯作者：
Huitema, Alwin D. R.
中科院分区：
文献类型：
--
作者：
Joerger, Markus;Ferreri, Andres J. M.;Huitema, Alwin D. R.
目的关于大剂量甲氨蝶呤(HDMTX)治疗原发中枢神经系统淋巴瘤的最佳剂量尚无共识。我们的目的是开发一种简便的给药算法，靶向AUCMTX在1000-1100 mmol L(-1)h范围内。方法从131名接受HDMTX的患者的汇集数据集中建立总体协变量模型，模拟1万名患者的浓度-时间曲线，并测试基于24 h MTX血药浓度的给药算法针对预先指定的AUC(MTX)的有效性。这些数据模拟包括个体间、时机间和剩余的未知变异性。患者接受了总共4个模拟周期的HDMTX，并调整了2至4个周期的MTX剂量。结果剂量算法提出了MTX剂量适应性，范围从+75%在MTXC24和Lt；0.5 mmolll(-1)到-35%在MTXC(24)和GT；12 mmolL(-1)。结果表明，在1000~1100 mmolMTX(-1)h内，受试者比例显著提高(标准剂量为11%，调整剂量为35%)，甲氨蝶呤暴露个体间变异性显著降低。结论基于甲氨蝶呤24 h血药浓度，提出了一种简单实用的甲氨蝶呤给药算法，数据模拟结果表明，该算法在提高甲氨蝶呤靶区受试者比例和降低甲氨蝶呤暴露个体变异性方面具有潜在的效果。这种剂量算法的临床益处应该在原发性中枢神经系统淋巴瘤(PCNSL)患者中进行评估。
AIMThere is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUCMTX in the range between 1000 and 1100 mmol l(-1) h.METHODSA population covariate model from a pooled dataset of 131 patients receiving HDMTX was used to simulate concentration-time curves of 10 000 patients and test the efficacy of a dosing algorithm based on 24 h MTX plasma concentrations to target the prespecified AUC(MTX). These data simulations included interindividual, interoccasion and residual unidentified variability. Patients received a total of four simulated cycles of HDMTX and adjusted MTX dosages were given for cycles two to four.RESULTSThe dosing algorithm proposes MTX dose adaptations ranging from + 75% in patients with MTX C24 < 0.5 mmol ll(-1) up to - 35% in patients with MTX C(24) > 12 mmol l(-1). The proposed dosing algorithm resulted in a marked improvement of the proportion of patients within the AUCMTX target between 1000 and 1100 mmol l(-1) h (11% with standard MTX dose, 35% with the adjusted dose) and a marked reduction of the interindividual variability of MTX exposure.CONCLUSIONSA simple and practical dosing algorithm for HDMTX has been developed based on MTX 24 h plasma concentrations, and its potential efficacy in improving the proportion of patients within a prespecified target AUCMTX and reducing the interindividual variability of MTX exposure has been shown by data simulations. The clinical benefit of this dosing algorithm should be assessed in patients with primary central nervous system lymphoma (PCNSL).