Pharmacokinetic and Pharmacodynamic Modeling of Anticancer Agents

为了优化治疗，需要对任何系统治疗的药代动力学有充分的了解。我们常规地对接受抗肿瘤活性测试的药物的药代动力学(PK)数据进行建模，并将其与活性和/或毒性相关(药效学建模)。该实验室目前正在合作进行80项临床试验，以确定新型化疗药物的临床药理学特征。我们使用隔间和非隔间的方法来定义代理的部署。对PK数据的分析(使用使用有效化验的样品分析提供的浓度测量)可以评估药物处置，包括药物的吸收、分布、代谢和排泄。对这些数据进行建模，基本上将这些生理过程描述为数学方程，从而允许在硅胶中优化给药(包括剂量和给药频率)。多年来，我们对以下化合物进行了群体药代动力学建模：去脂肽、罗米地平、索拉非尼、奥拉帕利布、多西紫杉醇与P-糖蛋白拮抗剂Tariquidar、TRC105和TRC102联合使用。米曲霉素、VT464和贝力诺的群体PK模型研究正在进行中。对TRC105在成人实体瘤患者中的I期研究进行了群体PK分析。TRC105是一种人/鼠嵌合的抗CD105的单抗，通过抑制内皮细胞的生长来抑制血管生成和肿瘤生长。该分析的特点是抗体的剂量特异性清除和靶向介导的处置。最后，最近的努力集中在建立群体PK模型，以了解米曲霉素在体内的处置动力学，从而最佳地优化剂量。此外，我们正在开发一个PK/PD模型，以了解贝力诺他汀在体内的处置动力学及其与药理作用的相关性，以基于某些协变量(如基因状态)最佳地优化剂量。为了进一步了解卡铂和奥拉帕利清除之间的机制关系，我们建立了一个群体PK模型，并用CPP进行了验证。CYP17抑制剂VT464正在开发中，用于治疗转移性去势抵抗前列腺癌。最初的非隔室分析显示，与第一次给药相比，稳态时的清除明显较慢，虽然不是明确的剂量依赖关系，但可能表明时间依赖的自体抑制。正在开发群体PK模型，以更好地了解药物的PK曲线，并评估该模型预测时间依赖和潜在剂量依赖的自身抑制的能力。

In order to optimize therapy, a full understanding of the pharmacokinetics of any systemic therapy is desired. We routinely model the pharmacokinetic (PK) data of agents being tested for antitumor activity and correlate that with activity and/or toxicity (pharmacodynamics modeling). The laboratory is currently collaborating on 80 clinical trials to characterize the clinical pharmacology of novel chemotherapy agents. We utilize compartmental and noncompartmental approaches to define the disposition of agents. Analysis of PK data (using concentration measurements provided by sample analysis using validated assays) allows for assessment of drug disposition, including the absorption, distribution, metabolism and excretion of a drug. Modeling this data, essentially describing these physiological processes as a mathematical equation, allows for optimization of drug administration (including dose and frequency of dosing,) in silico. Over the years, we have conducted population pharmacokinetic modeling of the following compounds: depsipeptide, romidepsin, sorafenib, olaparib, docetaxel in combination with the p-glycoprotein antagonist tariquidar, TRC105, and TRC102. Studies are ongoing for population PK modeling of mithramycin, VT464 and belinostat. A population PK analysis of a phase I study of TRC105 in adults with solid tumors was conducted. TRC105 is a human/murine chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth via endothelial cell growth inhibition. The analysis characterized dose-specific clearance and target-mediated disposition of the antibody. Finally, recent efforts have focused on building a population PK model to understand the disposition kinetics of mithramycin in the body to best optimize dose. In addition, we are developing a PK/PD model to understand the disposition kinetics of belinostat in the body and correlations with pharmacological effect to best optimize dose based on certain covariates such as genotype status. To further understand the mechanistic relationship between carboplatin and olaparib clearance, a population PK model was developed and validated by the CPP. The CYP17 inhibitor, VT464, is being developed for metastatic castrate-resistant prostate cancer. An initial noncompartmental analysis revealed a significantly slower clearance during steady-state compared to first dose, that while not explicitly dose-dependent, could indicated time-dependent autoinhibition. Population PK model is being developed to better understand the drug's PK profile and assess the model's ability to predict time-dependent, and potentially dose-dependent, autoinhibition.