Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Florida, Orlando, USA.
Institute for Therapeutic Innovation Department of Medicine Institute for Therapeutic Innovation, Orlando, Florida, USA.
AAPS J. 2021 Jan 6;23(1):18. doi: 10.1208/s12248-020-00542-0.
Dose-dependent life-threatening doxorubicin-induced cardiotoxicity (DIC) is a major clinical challenge that needs to be addressed. Here, we developed an integrated multiscale and translational quantitative systems toxicology and pharmacokinetic-toxicodynamic (QST-PK/TD) model for optimization of doxorubicin dosing regimens for early monitoring and minimization of DIC. A QST model was established by exposing human cardiomyocytes, AC16 cells, to doxorubicin over a time course, and measuring the dynamics of intracellular signaling proteins, AC16 cell viability and released biomarkers of cardiomyocyte injury such as the B-type natriuretic peptide (BNP). Experiments were scaled up to a three-dimensional and dynamic (3DD) cell culture system to evaluate DIC under various dosing regimens. The PK determinants of doxorubicin influencing DIC were identified in vitro and then translated to the in vivo setting through hybrid physiologically based PK (PBPK)/TD models using preclinical- and clinical-level data extracted from literature. The developed cellular-level QST model captured well the observed dynamics of intracellular proteins, AC16 cell viability and BNP kinetics. In the 3DD setting, dose fractionation of doxorubicin displayed a significant reduction in cardiotoxicity compared to single intravenous doses with equal exposure, implying doxorubicin peak concentrations as the PK determinant for DIC. The in vivo hybrid PBPK/TD models captured well doxorubicin PK and DIC. Peak doxorubicin concentrations correlated well with acute DIC for dose-fractionated regimens, while maximum 48-h moving average concentrations correlated with DIC for dose-fractionated and long-term infusion regimens in vivo. The developed multiscale and translational QST-PK/TD modeling platform may serve as an in silico tool for assessment of early toxicity and/or efficacy of developmental drugs in vitro.
剂量依赖性致死性多柔比星诱导的心脏毒性（DIC）是一个重大的临床挑战，需要加以解决。在这里，我们开发了一个综合的多尺度和转化的定量系统毒理学和药代动力学-毒性动力学（QST-PK/TD）模型，用于优化多柔比星给药方案，以进行早期监测和最小化 DIC。通过在时间过程中使人类心肌细胞 AC16 细胞暴露于多柔比星，建立了 QST 模型，并测量了细胞内信号蛋白、AC16 细胞活力和释放的心肌损伤生物标志物（如 B 型利钠肽（BNP））的动力学。实验扩展到一个三维和动态（3DD）细胞培养系统，以评估不同给药方案下的 DIC。在体外确定了影响 DIC 的多柔比星 PK 决定因素，然后通过使用来自文献的临床前和临床水平数据的混合生理基于 PK（PBPK）/TD 模型将其转化为体内环境。开发的细胞水平 QST 模型很好地捕捉了观察到的细胞内蛋白、AC16 细胞活力和 BNP 动力学的动力学。在 3DD 环境中，与具有相同暴露量的单次静脉内剂量相比，多柔比星的剂量分割显示出心脏毒性的显著降低，这意味着多柔比星峰值浓度是 DIC 的 PK 决定因素。体内混合 PBPK/TD 模型很好地捕捉了多柔比星 PK 和 DIC。对于剂量分割方案，多柔比星峰值浓度与急性 DIC 相关性良好，而对于剂量分割和长期输注方案，最大 48 小时移动平均浓度与体内 DIC 相关性良好。开发的多尺度和转化的 QST-PK/TD 建模平台可用作体外评估新型药物早期毒性和/或疗效的计算工具。
