SMARTc Unit, Centre de Recherche en Cancérologie de Marseille, U1068, Institut National de la santé et de la recherche médicale, Marseille, France.
Institut Paoli-Calmette, Marseille, France.
Cancer Chemother Pharmacol. 2019 Jan;83(1):27-42. doi: 10.1007/s00280-018-3722-5. Epub 2018 Nov 16.
FOLFIRINOX regimen is commonly used in colorectal and more recently pancreatic cancer. However, FOLFIRINOX induces significant and dose-limiting toxic effects leading to empirical dose reduction and sometimes treatment discontinuation. Model-based FOLFIRINOX regimen optimization might help improving patients' outcome. As a first step, the current review aims at bringing together all published population pharmacokinetics models for FOLFIRINOX anticancer drugs.
A literature search was conducted in the PubMed database from inception to February 2018, using the following terms: population pharmacokinetic(s), irinotecan, oxaliplatin, fluorouracil, FOLFIRI, FOLFOX, FOLFIRINOX. Only articles displaying nonlinear mixed effect models were included. Study description, pharmacokinetic parameter values and influential covariates are reported. For each model, the typical pharmacokinetic profile was simulated for the standard FOLFIRINOX protocol.
The FOLFIRINOX compounds have been studied only separately so far. A total of six articles were retained for 5-fluorouracil, 6 for oxaliplatin and 5 for irinotecan (also including metabolites). Either one- or two-compartment models have been described for 5-fluorouracil, while two- or three-compartment models were reported for oxaliplatin and irinotecan pharmacokinetics. Non-linear elimination was sometimes reported for 5-fluorouracil. Sex and body size were found as influential covariates for all molecules in some publications. Despite some differences in model structures and parameter values, the simulated profiles and subsequent exposure were consistent between studies.
The current review allows for a global understanding of FOLFIRINOX pharmacokinetics, and will provide a basis for further development of pharmacokinetics-pharmacodynamics-toxicity models for model-driven FOLFIRINOX protocol optimization to reach the best benefit-to-risk ratio.
FOLFIRINOX 方案常用于结直肠癌，最近也用于胰腺癌。然而，FOLFIRINOX 会引起明显的剂量限制毒性作用，导致经验性剂量减少，有时甚至停止治疗。基于模型的 FOLFIRINOX 方案优化可能有助于改善患者的预后。作为第一步，本综述旨在汇集所有已发表的 FOLFIRINOX 抗癌药物的群体药代动力学模型。
从建库到 2018 年 2 月，在 PubMed 数据库中进行了文献检索，使用了以下术语：群体药代动力学、伊立替康、奥沙利铂、氟尿嘧啶、FOLFIRI、FOLFOX、FOLFIRINOX。仅纳入显示非线性混合效应模型的文章。报告研究描述、药代动力学参数值和有影响的协变量。对于每个模型，均根据标准 FOLFIRINOX 方案模拟了典型的药代动力学特征。
迄今为止，FOLFIRINOX 化合物仅分别进行了研究。共保留了 6 篇关于 5-氟尿嘧啶的文章，6 篇关于奥沙利铂的文章，5 篇关于伊立替康（包括代谢物）的文章。5-氟尿嘧啶的描述采用单室或双室模型，奥沙利铂和伊立替康药代动力学采用双室或三室模型。在一些出版物中，5-氟尿嘧啶的消除有时被报告为非线性。在一些出版物中，性别和身体大小被发现是所有分子的有影响的协变量。尽管模型结构和参数值存在一些差异，但在研究之间，模拟的曲线和随后的暴露是一致的。
本综述使人们对 FOLFIRINOX 药代动力学有了全面的了解，为进一步开发基于药代动力学-药效学-毒性模型以优化基于模型的 FOLFIRINOX 方案提供了基础，以达到最佳的获益-风险比。
