Krzyzanski Wojciech, Perez-Ruixo Juan Jose, Harrold John
Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
Clinical Pharmacology, Modeling and Simulation, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91360, USA.
J Pharmacokinet Pharmacodyn. 2015 Dec;42(6):709-20. doi: 10.1007/s10928-015-9440-2. Epub 2015 Sep 4.
A mechanistic model describing the effects of chemotherapy and radiation on platelet counts and endogenous thrombopoietin (eTPO) in mice was developed. Thrombocytopenia was induced in mice by injection of carboplatin followed by the whole body irradiation on days 0, 28, and 56, with platelet and eTPO samples collected over 84 days. The pharmacodynamic model consisted of a series of aging compartments representing proliferating megakaryocyte precursors, megakaryocytes, and platelets with possible eTPO clearance through internalization. The cytotoxic effects of treatment were described by the kinetics of the effect (K-PD) model, and stimulation of platelet production by eTPO was considered to be driven by receptor occupancy. The proposed PD model adequately described the platelet counts and eTPO concentrations in mice by accounting for nadirs and peaks of platelet count, and rebounds in eTPO time course profiles. The estimates of model parameters were in good agreement with their physiological values reported in literature for mice with platelet lifespan of 4.3 days and 185 cMpl receptors per platelet. The predicted duration of the treatment effect was 0.82 h (approximately 5 carboplatin half-lives in mice). The data was not informative about the eTPO stimulatory effect as the nominal precursor production rate was sufficient to account for platelet response to treatment. The model quantified the inverse relationship between eTPO levels and platelet counts and offered an explanation of the tolerance effect observed in the eTPO data. The simulated rebound in free receptors levels correlated with rebounds in eTPO levels. The model suggests that the duration of the toxic effects is determined by the turnover of the proliferating cells in the bone marrow. This indicates that the lifespan of the target cells (megakaryocyte precursors, megakaryocytes and platelets) is a key determinant in the duration of both drug exposure and toxicity due to treatment. The model can be extended to account for pharmacokinetics of exogenous drugs and be applied to analysis of human data.
建立了一个描述化疗和放疗对小鼠血小板计数及内源性血小板生成素（eTPO）影响的机制模型。通过在第0、28和56天注射卡铂后进行全身照射，诱导小鼠血小板减少，并在84天内收集血小板和eTPO样本。药效学模型由一系列代表增殖的巨核细胞前体、巨核细胞和血小板的衰老隔室组成，可能通过内化清除eTPO。治疗的细胞毒性作用由效应动力学（K-PD）模型描述，eTPO对血小板生成的刺激被认为是由受体占有率驱动的。所提出的药效学模型通过考虑血小板计数的最低点和峰值以及eTPO时间进程曲线中的反弹，充分描述了小鼠的血小板计数和eTPO浓度。模型参数估计值与文献报道的血小板寿命为4.3天且每个血小板有185个cMpl受体的小鼠的生理值高度一致。预测的治疗效果持续时间为0.82小时（约为小鼠体内卡铂半衰期的5倍）。由于名义前体产生率足以解释血小板对治疗的反应，因此这些数据对于eTPO刺激作用并无信息价值。该模型量化了eTPO水平与血小板计数之间的反比关系，并对eTPO数据中观察到的耐受效应提供了解释。模拟的游离受体水平反弹与eTPO水平反弹相关。该模型表明，毒性作用的持续时间由骨髓中增殖细胞的更新率决定。这表明靶细胞（巨核细胞前体、巨核细胞和血小板）的寿命是药物暴露持续时间和治疗毒性的关键决定因素。该模型可扩展以考虑外源性药物的药代动力学，并应用于人类数据分析。
