Jeffrey G. Supko, PhD
Associate Professor of Medicine
Harvard Medical School
Clinical Pharmacology Laboratory
The Clinical Pharmacology Laboratory (CPL) provides clinical investigators in the Massachusetts General Hospital Cancer Center with the capabilities required to undertake the pharmacokinetic studies that are an important component of early phase clinical trials of investigational anticancer agents. An understanding of the pharmacokinetic behavior of an drug facilitates the rational determination of the dose, route and schedule of administration that maximizes the potential for therapeutic effectiveness while minimizing the likelihood of serious adverse effects. Acquiring pharmacokinetic data necessarily depends upon the ability to accurately and specifically measure the a drug or active metabolites in biological fluids. The development, validation and application of bioanalytical methods, especially those based upon high performance liquid chromatography with mass spectrometric detection (LC/MS), is a major activity of the laboratory. The CPL has been instrumental in characterizing the pharmacokinetic behavior of many structurally diverse chemotherapeutic agents. The two recently completed studies that are summarized below illustrate the important role of pharmacokinetic studies in the development and evaluation of new strategies for treating solid malignancies and brain tumors.
Dr. Carolyn Krasner (Gillette Center for Gynecologic Oncology) undertook a Phase II trial to evaluate intraperitoneal (IP) administration of paclitaxel and carboplatin in patients with optimally debulked ovarian cancer. Determining the pharmacokinetics of both agents was an important secondary objective of the study because adequate systemic drug exposure is considered to be essential for eliciting the maximum therapeutic benefit of IP chemotherapy. Paclitaxel 60 mg/m2 was given once every week and carboplatin (6 mgmin/mL) was given once every three weeks. Both agents were infused over 1 hour, IV in the first cycle to determine absolute bioavailability in each patient and IP in the five subsequent 21-day cycles. Paclitaxel and free platinum was determined by LC/MS and flameless atomic absorption spectrometry, respectively, in plasma samples collected after giving the first dose in cycles 1, 2 and 6. A potentially effective pattern of systemic exposure to both agents was achieved in a majority of the 40 patients evaluated. The time that plasma levels of paclitaxel exceeded the 0.05 µM threshold concentration associated with clinical effectiveness was actually greater for two weekly doses of 60 mg/m2 IP than standard treatment (a single 135 mg/m2 dose given by 24 hour IV infusion once every three weeks). Pharmacokinetic-guided dose adjustment may be appropriate for the subgroup of patients exhibiting inadequate systemic absorption of IP paclitaxel.
The blood brain barrier (BBB) restricts the access of many drugs to the brain and is considered to be a major contributing factor to the poor overall response of brain tumors to systemic chemotherapy. Determining whether potentially effective drug concentrations can be achieved within brain tumors would provide a rational basis for selecting agents for Phase II trials. However, characterizing drug distribution to brain tumors in patients is extremely difficult. The NABTT Consortium undertook a study to assess the feasibility of using microdialysis, a technique that enables low molecular weight compounds to be sampled in extracellular fluid (ECF), in patients with high grade gliomas. After obtaining an MRI scan to define the contrast enhancing region of the tumor, a microdialysis catheter was inserted into the tumor bed in patients undergoing a clinically indicated stereotactic biopsy or resection. The catheter was perfused with Ringer's solution at 1µl/min and perfusate was collected at 30 min intervals from 1 hpir before to 24 hour after giving methotrexate (MTX) 12 g/m2 as a 4 hour IV infusion. The MTX concentration in serial plasma samples collected during this same period and microdialysis perfusate was determined by LC/MS. Although the plasma pharmacokinetics of MTX was similar in each of the 4 patients evaluated, there were distinct differences in the time course of MTX in brain ECF associated with the location of the microdialysis probe (determined by CT scan). MTX levels in ECF were considerably greater in contrast enhancing regions of the tumor as compared to noncontrast enhancing tissue, consistent with the integrity of the BBB. Microdialysis is a very informative technique for assessing whether adequate drug concentrations are achieved and sustained for a sufficient period of time in the proliferating edge of a tumor, where the BBB is intact. Properly assessing microdialysis data requires establishing BBB integrity where the probe is located by contrast enhanced MRI.
Jeffrey G. Supko, PhD