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。我们常规地对被测试抗肿瘤活性的药物的药代动力学数据进行建模，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40项临床试验，以表征新型化疗药物的临床药理学。对药代动力学数据的分析(使用样品分析提供的浓度测量，使用有效的分析方法)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)。在一项研究食物对药物处置影响的临床试验中，组蛋白去乙酰酶抑制剂MS-275的药代动力学已经完成。在口服MS-275之前和之后，每周一次的禁食被发现导致药物暴露的个体间变异性降低。利用来自多个CCR临床试验的数据对Depsi多肽(FK228)进行群体药代动力学建模，结果表明，ABCB1、CYP3A4和CYP3A5基因的常见多态对FK228的药代动力学没有显著影响。此外，年龄、肾功能、身体大小和成分预计对全身暴露于FK228的影响很小或没有影响。所建立的群体药代动力学模型已得到验证，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模型目前正在进行中，咪达唑仑通常作为评估CYP3A活性的探针药物。我们最近完成了ABI-007(Abraxane)的临床研究，这是一种白蛋白结合的紫杉醇纳米粒配方，不含任何额外的辅料。我们假设，与传统的溶剂型制剂(紫杉醇)相比，这种处方的改变改变了紫杉醇的全身处置，并导致了药物耐受性的改善。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)或紫杉醇(175 mg/m2，3小时输注)。在周期1之后，患者交叉接受替代治疗。对紫杉醇的第一周期和ABI-007的前两周期进行了药代动力学研究。17名患者接受了治疗，其中14名患者分别接受了ABI-007和紫杉醇至少一个周期的治疗。在第一个周期和第二个周期之间，ABI-007的药代动力学没有发现变化，这表明受试者内的可变性有限。尽管剂量不同，但两种制剂之间的总药物暴露是相似的(P=0.55)。然而，在服用ABI-007后，由于游离部分的增加(0.063 0.021比0.024 0.009，P&lt；0.001)，暴露于无结合紫杉醇的量显著增加。这项研究表明，紫杉醇的处置取决于所使用的配方，具有相当大的变异性。由于全身暴露于未结合的紫杉醇可能是肿瘤摄取背后的驱动力，这些发现至少部分解释了先前的观察结果，即与紫杉醇相比，ABI-007的应用与增强抗肿瘤疗效有关。罗米地辛在皮肤T细胞淋巴瘤和复发性外周T细胞淋巴瘤患者中的群体药代动力学。罗米地辛是一种有效的组蛋白脱乙酰酶抑制剂，正在临床开发中。本研究的目的是评估人口统计学、临床和药物遗传学协变量对罗米地平在T细胞淋巴瘤患者中的药代动力学的影响。对98名参加II期研究的患者进行了药代动力学评估，这些患者在第一个治疗周期的第一天接受了14或18 mg/m2的罗米地辛4小时输注。使用非线性混合效应建模方法进行群体建模，以探索CYP3A4、CYP3A5、SLCO1B3和ABCB1基因的多态变异的影响，所有这些基因都编码与罗米地辛处置有关的基因。具有线性动力学的二室模型很好地描述了罗米地辛的分布。人群清除量为15.9 L/小时，患者间变异为37%。ABCB1 2677G&GT；T/A变异等位基因倾向于清除量减少，组织分布体积减少，但没有统计学意义的支持。CYP3A4/5和SCLO1B3基因变异对全身暴露无影响。群体药代动力学分析表明，罗米地辛的药代动力学存在适度的个体间变异性，没有临床相关的协变量与该人群中罗米非辛的不明原因的药代动力学变异性有关。

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 40 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 <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. Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Romidepsin is a potent histone deacetylase inhibitor under clinical development. The objective of this study was to evaluate the effect of demographic, clinical, and pharmacogenetic covariates on the pharmacokinetics of romidepsin in patients with T-cell lymphoma. Pharmacokinetic assessment was done in 98 patients enrolled in a phase II study who received 14 or 18 mg/m2 of romidepsin as a 4-hour infusion on day 1 during their first treatment cycle. Population modeling was done using a nonlinear mixed effects modeling approach to explore the effects of polymorphic variations in CYP3A4, CYP3A5, SLCO1B3, and ABCB1, all of which encode genes thought to be involved in romidepsin disposition. A two-compartment model with linear kinetics adequately described the romidepsin disposition. Population clearance was 15.9 L/h with between-patient variability of 37%. ABCB1 2677G>T/A variant alleles tended toward a reduced clearance and lower volume of tissue distribution, but this was not supported by a statistical significance. Genetic variations in CYP3A4/5 and SCLO1B3 had no effect on the systemic exposure. The population pharmacokinetic analysis indicates moderate interindividual variability in romidepsin pharmacokinetics and no clinically relevant covariates associated with the unexplained pharmacokinetic variability of romidepsin in this population.