Mangas-Sanjuan Víctor, Buil-Bruna Núria, Garrido María J, Soto Elena, Trocóniz Iñaki F
Department of Engineering, Department of Pharmacy and Pharmaceutical Technology Area, University of Miguel Hernández de Elche, San Juan de Alicante, Alicante, Spain (V.M.-S.); Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Navarra, Spain (N.B.-B., M.J.G., I.F.T.); and Pharmacometrics, Pfizer, Sandwich, United Kingdom (E.S.).
Department of Engineering, Department of Pharmacy and Pharmaceutical Technology Area, University of Miguel Hernández de Elche, San Juan de Alicante, Alicante, Spain (V.M.-S.); Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Navarra, Spain (N.B.-B., M.J.G., I.F.T.); and Pharmacometrics, Pfizer, Sandwich, United Kingdom (E.S.)
J Pharmacol Exp Ther. 2015 Jul;354(1):55-64. doi: 10.1124/jpet.115.223776. Epub 2015 May 6.
The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n = 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, FProl (the fraction of proliferative [Prol] cells that enters into the maturation chain) and kcycle (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of FProl and kcycle were 0.58 and 1.94 day(-1), respectively. The new model could properly describe the neutropenic effects of diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.
当前的工作将骨髓区室中发生的细胞周期动力学整合为中性粒细胞减少效应的半机制药代动力学/药效学模型结构中的关键要素，旨在使用同一组与系统和药物相关的参数，描述晚期实体瘤患者（n = 111）在不同给药方案下给予抗癌药物地氟莫特坎（9,10 - 二氟高喜树碱）后收集的中性粒细胞减少的纵向数据。为实现这一目标，中性粒细胞减少模型的总体框架得到了扩展，包括一个类似于细胞周期动力学的额外生理过程。所提出模型的主要假设如下：在干细胞区室中，增殖细胞和静止细胞共存，只有处于增殖状态的细胞对药物作用敏感并能够进入成熟链。细胞周期动力学由两个新参数表征，FProl（进入成熟链的增殖[Prol]细胞的比例）和kcycle（控制干细胞区室中细胞周期动力学的一级速率常数）。自举分析结果表明这两个模型参数均可识别，并且它们的估计值得到了文献数据的支持。FProl和kcycle的估计值分别为0.58和1.94天⁻¹。新模型能够恰当地描述在非常不同的给药方案下地氟莫特坎的中性粒细胞减少效应，并且可用于探索给药方案依赖性对中性粒细胞减少预测的潜在影响。
