He Hua, Cao Yanguang
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
J Pharmacokinet Pharmacodyn. 2017 Oct;44(5):491-501. doi: 10.1007/s10928-017-9540-2. Epub 2017 Aug 31.
Conventional maximum tolerated doses (MTD) in chemotherapy are recently challenged by an alternative dosing method with low doses and high dosing frequency (LDHF). Still, it remains unclear which chemotherapies would potentially benefit from LDHF. The pharmacokinetic (PK) differences between MTD and LDHF are drug exposure magnitude (concentration) and exposure duration (time), two fundamental PK elements that are associated with the pharmacodynamics (PD) of chemotherapies. Here we hypothesized that quantitatively analyzing the contribution of each PK element to the overall cytotoxic effects would provide insights to the selection of the preferred chemotherapeutic dosing. Based on in vitro cytotoxic data, we developed a cellular PD model, which assumed that tumor cells were generally comprised of two subpopulations that were susceptible to either concentration- or time-dependent cytotoxicity. The developed PD model exhibited high flexibility to describe diverse patterns of cell survival curves. Integrated with a PK model, the cellular PD model was further extended to predict and compare the anti-tumor effect of paclitaxel in two dosing regimens: multiple MTD bolus and continuous constant infusion (an extreme LDHF). Our simulations of paclitaxel in treatment of three types of cancers were consistent with clinical observations that LDHF yielded higher patient efficacy than MTD. Our further analysis suggested that the ratio between drug steady-state concentrations and its cytotoxic sensitivity (C /KC ) was a critical factor that largely determines favored dosing regimen. LDHF would produce higher efficacy when the ratio C /KC is greater than 1. Otherwise MTD was favored. The developed PD model presented an approach simply based on in vitro cytotoxic data to predict the potentially favored chemotherapeutic dosing between MTD and LDHF.
化疗中的传统最大耐受剂量（MTD）最近受到了一种低剂量高给药频率（LDHF）的替代给药方法的挑战。然而，目前仍不清楚哪些化疗药物可能从LDHF中获益。MTD和LDHF之间的药代动力学（PK）差异在于药物暴露量（浓度）和暴露持续时间（时间），这两个基本的PK要素与化疗的药效学（PD）相关。在此，我们假设定量分析每个PK要素对总体细胞毒性作用的贡献，将为选择首选的化疗给药方式提供见解。基于体外细胞毒性数据，我们开发了一种细胞PD模型，该模型假设肿瘤细胞通常由两个亚群组成，分别对浓度依赖性或时间依赖性细胞毒性敏感。所开发的PD模型在描述细胞存活曲线的不同模式方面具有高度灵活性。与PK模型相结合，细胞PD模型进一步扩展，以预测和比较紫杉醇在两种给药方案中的抗肿瘤效果：多次MTD推注和持续恒速输注（一种极端的LDHF）。我们对紫杉醇治疗三种癌症类型的模拟结果与临床观察一致，即LDHF比MTD产生更高的患者疗效。我们的进一步分析表明，药物稳态浓度与其细胞毒性敏感性之比（C /KC ）是一个关键因素，在很大程度上决定了首选的给药方案。当C /KC 比值大于1时，LDHF将产生更高的疗效。否则，MTD更受青睐。所开发的PD模型提出了一种简单基于体外细胞毒性数据的方法，以预测MTD和LDHF之间潜在更受青睐的化疗给药方式。
