Pharmacokinetic and Pharmacodynamic Modeling of Anticancer Agents

为了优化治疗，需要充分了解任何全身治疗的药代动力学。我们通常对正在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。药代动力学数据分析（使用样品分析提供的浓度测量，使用验证的测定法）允许评估药物处置，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，从而可以在计算机上优化药物给药（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，组蛋白去乙酰化酶抑制剂MS-275的药代动力学已经完成。研究发现，在口服MS-275之前和之后立即禁食，每周一次，可减少药物暴露的个体差异。利用多个CCR临床试验数据建立的FK228的群体药代动力学模型表明，ABCB1、CYP3A4和CYP3A5基因的常见多态性对FK228的药代动力学没有明显影响。此外，年龄、肾功能、体型和身体成分预计对FK228的全身暴露影响很小或没有影响。建立的人群药代动力学模型得到了验证，可用于未来临床试验的模拟和预测。咪达唑仑的群体药代动力学模型目前正在进行中，咪达唑仑通常被用作评估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颗粒制剂，不含任何其他辅料。我们假设，与传统的溶剂型制剂（紫杉醇）相比，这种配方的改变改变了紫杉醇的系统配置，并导致药物耐受性的提高。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）。在第1周期后，患者转入替代治疗。对紫杉醇第一个周期和ABI-007前两个周期进行了药代动力学研究。17例患者接受治疗，其中14例分别接受ABI-007和紫杉醇至少一个周期的治疗。在第一个和第二个周期之间，ABI-007的药代动力学没有变化，这表明受试者体内的变异性有限。尽管剂量不同，但两种制剂的总药物暴露量具有可比性（P= 0.55）。然而，在ABI-007给药后，由于游离分数增加，未结合紫杉醇的暴露量显著增加（0.063 0.021 vs 0.024 0.009, P <0.001）。这项研究表明，紫杉醇处置是受到相当大的可变性取决于所使用的配方。由于全身暴露于非结合紫杉醇可能是肿瘤摄取背后的驱动力，这些发现至少部分地解释了先前的观察结果，即与紫杉醇相比，ABI-007的施用与增强的抗肿瘤功效相关。罗米地辛在皮肤t细胞淋巴瘤和复发外周t细胞淋巴瘤患者中的群体药代动力学。罗米地辛是一种临床开发中的有效组蛋白去乙酰化酶抑制剂。本研究的目的是评估人口统计学、临床和药物遗传协变量对罗米地辛在t细胞淋巴瘤患者体内药代动力学的影响。在一项II期研究中，98名患者在第一个治疗周期的第一天接受14或18 mg/m2的罗米地辛作为4小时输注，进行了药代动力学评估。种群建模使用非线性混合效应建模方法来探索CYP3A4、CYP3A5、SLCO1B3和ABCB1多态性变异的影响，所有这些基因编码被认为与罗米地辛处置有关。线性动力学的两室模型充分描述了罗米地辛的处置。人群清除率为15.9 L/h，患者间变异性为37%。ABCB1 2677G&gt；T/A变异等位基因有清除率降低、组织分布体积减小的趋势，但没有统计学意义支持。CYP3A4/5和SCLO1B3的遗传变异对全身暴露没有影响。人群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罗米地辛在该人群中无法解释的药代动力学变异性相关。

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.