University of Lyon, Lyon, F-69007, France; CNRS, GATE Lyon Saint-Etienne, F-69130, France.
emlyon business school, Écully, F-69130, France; ETH Zurich, Zurich, CH-8092, Switzerland.
PLoS One. 2018 Jun 26;13(6):e0199076. doi: 10.1371/journal.pone.0199076. eCollection 2018.
We determine an optimal protocol for temozolomide using population variability and dynamic optimization techniques inspired by artificial intelligence. We use a Pharmacokinetics/Pharmacodynamics (PK/PD) model based on Faivre and coauthors (Faivre, et al., 2013) for the pharmacokinetics of temozolomide, as well as the pharmacodynamics of its efficacy. For toxicity, which is measured by the nadir of the normalized absolute neutrophil count, we formalize the myelosuppression effect of temozolomide with the physiological model of Panetta and coauthors (Panetta, et al., 2003). We apply the model to a population with variability as given in Panetta and coauthors (Panetta, et al., 2003). Our optimization algorithm is a variant in the class of Monte-Carlo tree search algorithms. We do not impose periodicity constraint on our solution. We set the objective of tumor size minimization while not allowing more severe toxicity levels than the standard Maximum Tolerated Dose (MTD) regimen. The protocol we propose achieves higher efficacy in the sense that -compared to the usual MTD regimen- it divides the tumor size by approximately 7.66 after 336 days -the 95% confidence interval being [7.36-7.97]. The toxicity is similar to MTD. Overall, our protocol, obtained with a very flexible method, gives significant results for the present case of temozolomide and calls for further research mixing operational research or artificial intelligence and clinical research in oncology.
我们使用基于 Faivre 等人（Faivre 等人，2013）的 Faivre 药代动力学/药效动力学（PK/PD）模型来确定替莫唑胺的最佳方案，该模型基于替莫唑胺的药代动力学和其疗效的药效动力学。对于毒性，这是通过归一化绝对中性粒细胞计数的最低点来衡量的，我们用 Panetta 等人（Panetta 等人，2003）的生理模型来形式化替莫唑胺的骨髓抑制作用。我们将该模型应用于 Panetta 等人（Panetta 等人，2003）中给出的具有变异性的人群中。我们的优化算法是蒙特卡罗树搜索算法类中的一个变体。我们不对解决方案施加周期性约束。我们将肿瘤大小最小化的目标设定为不允许毒性水平超过标准最大耐受剂量（MTD）方案。我们提出的方案在肿瘤大小缩小方面具有更高的疗效，即与通常的 MTD 方案相比，在 336 天后肿瘤大小缩小了约 7.66。毒性与 MTD 相似。总的来说，我们的方案是使用非常灵活的方法获得的，对于目前替莫唑胺的情况，结果非常显著，并呼吁进一步研究将运筹学或人工智能与肿瘤学的临床研究相结合。
