Pharmacokinetic and Pharmacodynamic Modeling of Anticancer Agents

为了优化治疗，充分了解任何药物的药代动力学 需要全身治疗。我们常规地模拟药物的药代动力学数据， 测试抗肿瘤活性并将其与活性和/或毒性相关联 （药效学建模）。该实验室目前正在合作进行45项临床试验 描述新型化疗药物的临床药理学特征。分析 药代动力学数据（使用浓度测量，通过使用 经验证的测定）允许评估药物处置，包括吸收， 分布、代谢和排泄。对这些数据进行建模， 这些生理过程作为数学方程，允许优化药物 给药（包括剂量和给药频率）。药代动力学已经 完成了组蛋白去乙酰化酶抑制剂MS-275的临床试验， 食物对药物处置的影响在MS-275之前和之后立即禁食， 口服给药，每周一次的时间表，被发现导致减少 药物暴露的个体间差异。群体药代动力学模型 使用来自多个CCR临床试验的数据确定， ABCB 1、CYP 3A 4和CYP 3A 5基因的多态性不会明显影响 FK 228的药代动力学。此外，年龄、肾功能、身体大小和组成是 预计对FK 228的全身暴露量影响很小或没有影响。发达 群体药代动力学模型得到验证，可用于未来的临床试验 模拟和预测。咪达唑仑的群体药代动力学建模，通常 作为探针药物给药，用于评估CYP 3A活性，目前正在进行。我们最近 完成了ABI-007（Abraxane）的临床研究，ABI-007是一种白蛋白结合的纳米颗粒制剂， 紫杉醇，不含任何额外的赋形剂。我们假设， 与常规药物相比， 溶剂型制剂（紫杉醇），并导致药物耐受性的改善。患者 恶性实体瘤患者随机接受推荐的单药剂量 ABI-007（260 mg/m2，30分钟输注）或泰素（175 mg/m2，3小时输注）。 第1周期后，患者交叉接受替代治疗。药代动力学研究 对紫杉醇的第一个周期和ABI-007的前两个周期进行。十七 14例患者接受ABI-007和Taxol各至少一个周期的治疗。没有 ABI-007药代动力学在第一个和第二个周期之间发生变化，表明 受试者内变异性有限。两者的总药物暴露量相当 尽管存在剂量差异，但制剂中的剂量差异显著（P= 0.55）。然而，暴露于未结合的紫杉醇 ABI-007给药后，由于游离分数增加， （0.063 +/- 0.021 vs 0.024 +/- 0.009，P小于0.001）。这项研究表明 紫杉醇的分布具有相当大的可变性， 使用的配方。由于全身暴露于未结合紫杉醇可能是 在肿瘤摄取的背后，这些发现至少部分解释了以前的观察结果， ABI-007的给药与增强的抗肿瘤功效相关， 紫杉醇

In order to optimize therapy, a full understanding of the pharmacokinetics of any systemic therapy is desired. We routinely model the pharmacokinetic data of agents being tested for antitumor activity and correlate that with activity and/or toxicity (pharmacodynamics modeling). The laboratory is currently collaborating on 45 clinical trials to characterize the clinical pharmacology of novel chemotherapy agents. Analysis of pharmacokinetic 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. Pharmacokinetics have been completed for the histone deacetylase inhibitor MS-275, in a clinical trial which investigated the effects of food on drug disposition. Fasting prior to and immediately after MS-275 was administered orally, on a once-weekly schedule, was found to result in decreased interindividual variability in drug exposure. Population pharmacokinetic modeling of Depsipeptide (FK228) using data from multiple CCR clinical trials determined that common polymorphisms in the ABCB1, CYP3A4 and CYP3A5 genes do not appreciably influence the pharmacokinetics of FK228. Furthermore, age, renal function, and body size and composition are anticipated to have little or no impact on the systemic exposure to FK228. The developed population pharmacokinetic model was validated and can be used for the future clinical trials simulation and prediction. Population pharmacokinetic modeling of midazolam, often administered as a probe drug for assessing CYP3A activity, is currently ongoing. We recently completed a clinical study of ABI-007 (Abraxane), an albumin-bound nanoparticle formulation of paclitaxel, devoid of any additional excipients. We hypothesized that this change in formulation alters the systemic disposition of paclitaxel compared with conventional solvent-based formulations (Taxol), and leads to improved tolerability of the drug. Patients with malignant solid tumors were randomized to receive the recommended single agent dose of ABI-007 (260 mg/m2 as a 30 minute infusion) or Taxol (175 mg/m2 as a 3 hour infusion). Following cycle 1, patients crossed over to the alternate treatment. Pharmacokinetic studies were carried out for the first cycle of Taxol and the first two cycles of ABI-007. Seventeen patients were treated, with 14 receiving at least one cycle each of ABI-007 and Taxol. No change in ABI-007 pharmacokinetics was found between the first and second cycles, suggesting limited intrasubject variability. Total drug exposure was comparable between the two formulations (P= 0.55) despite the dose difference. However, exposure to unbound paclitaxel was significantly higher following ABI-007 administration, due to the increased free fraction (0.063 +/- 0.021 vs 0.024 +/- 0.009, P less than 0.001). This study demonstrates that paclitaxel disposition is subject to considerable variability depending on the formulation used. Since systemic exposure to unbound paclitaxel is likely a driving force behind tumoral uptake, these findings explain, at least in part, previous observations that the administration of ABI-007 is associated with augmented antitumor efficacy as compared with Taxol.