Pharmacokinetic and Pharmacodynamic Modeling of Anticancer Agents

点击翻译按钮获取中文摘要

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.