从大鼠到人类的卡培他滨和奥沙利铂联合化疗中用于剂量优化的骨髓抑制药代动力学-毒效学转化模型。

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Shinji Kobuchi, Mayuka Arimoto, Yukako Ito
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引用次数: 0

摘要

XELOX疗法由卡培他滨和奥沙利铂组成,是结直肠癌的标准一线化疗方案。然而,它的骨髓抑制作用给临床治疗带来了挑战。结合药代动力学(PK)和毒理学(TD)的数学建模是优化给药策略和降低毒性的一种可行方法。本研究旨在利用大鼠数据建立一个 PK-TD 转化模型,为人类的给药策略和 TD 影响提供依据。给大鼠服用卡培他滨、奥沙利铂或XELOX联合方案,并收集PK和TD数据。PK 参数采用连续分区分析法进行分析,而 TD 反应则采用 Friberg 半生理模型进行评估。基于毒性强度的提名图推荐了最佳用药策略。利用 PK-TD 混合模型的转化建模技术来预测临床反应。PK-TD 模型成功预测了单一疗法和 XELOX 联合疗法后大鼠血液学反应的时程曲线。同时服用卡培他滨和奥沙利铂会对淋巴细胞减少产生交互影响。为避免出现严重的淋巴细胞减少症,基于模型推荐的剂量减少率组合分别为卡培他滨和奥沙利铂剂量的 40% 和 60%。目前的转化模型技术利用大鼠数据成功模拟了患者血细胞计数的时程曲线和置信区间。我们的研究为 XELOX 治疗方案中每种药物的剂量优化策略提供了宝贵的见解,并强调了转化模型在改善患者预后方面的潜力。除剂量确定外,这些数据还将为推进肿瘤学药物开发过程奠定基础。意义声明 本研究引入了一种新颖的转化建模方法,以大鼠PK-TD模型为基础,优化XELOX方案治疗结直肠癌的剂量策略。我们的研究结果强调了对淋巴细胞减少症的交互影响,并提出了基于毒性强度的减量提名图,从而推动了精准医疗的发展。这种转化建模范例增强了我们对药物相互作用的理解,为接受 XELOX 治疗的患者提供了一种定制剂量、最小化血液毒性和改善治疗效果的工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Translational Pharmacokinetic-Toxicodynamic Model of Myelosuppression for Dose Optimization in Combination Chemotherapy of Capecitabine and Oxaliplatin from Rats to Humans.

XELOX therapy, which comprises capecitabine and oxaliplatin, is the standard first-line chemotherapeutic regimen for colorectal cancer. However, its myelosuppressive effects pose challenges for its clinical management. Mathematical modeling combining pharmacokinetics (PK) and toxicodynamics (TD) is a promising approach for optimizing dosing strategies and reducing toxicity. This study aimed to develop a translational PK-TD model using rat data to inform dosing strategies and TD implications in humans. The rats were administered capecitabine, oxaliplatin, or XELOX combination regimen, and PK and TD data were collected. PK parameters were analyzed using sequential compartment analysis, whereas TD responses were assessed using Friberg's semiphysiological model. A toxicity intensity-based nomogram recommends optimal dosing strategies. Translational modeling techniques using the hybrid PK-TD model were employed to predict clinical responses. The PK-TD model successfully predicted the time-course profiles of hematological responses in rats following monotherapy and XELOX combination treatment. Interactive effects on lymphocytopenia were identified with the coadministration of capecitabine and oxaliplatin. A model-based recommended combination of the dose reduction rate for escaping severe lymphocytopenia was proposed as 40% and 60% doses of capecitabine and oxaliplatin, respectively. The current translational model techniques successfully simulated the time-course profiles of blood cell counts with confidence intervals in patients using rat data. Our study provides valuable insights into dose optimization strategies for each individual drug within the XELOX regimen and underscores the potential of translational modeling to improve patient outcomes. In addition to dose determination, these data will lay the groundwork for advancing drug development processes in oncology. SIGNIFICANCE STATEMENT: This study introduced a novel translational modeling approach rooted in a rat PK-TD model to optimize dosing strategies for the XELOX regimen for colorectal cancer treatment. Our findings highlight the interactive effects on lymphocytopenia and suggest a toxicity intensity-based nomogram for dose reduction, thus advancing precision medicine. This translational modeling paradigm enhances our understanding of drug interactions, offering a tool to tailor dosing, minimize hematological toxicity, and improve therapeutic outcomes in patients undergoing XELOX therapy.

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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
期刊介绍: A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.
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