May Core Spotlight: Clinical Pharmacology
In this DF/HCC Core Spotlight, we present the DF/HCC Clinical Pharmacology Core, which offers services that are required to undertake pharmacokinetic studies during early phase clinical trials and preclinical investigations. The Core is located on the 10th floor of the Jackson Building on the MGH main campus. It has extensive expertise with LC-MS/MS based analytical methods to measure drugs that are low molecular weight organic molecules, including peptides and small proteins, in biological fluids and tissue. Assays that have been appropriately validated for clinical drug level monitoring and are readily available for application in new studies have been established for nearly 50 investigational and approved anticancer drugs. Extensive quality assurance procedures have been implemented to assure that laboratory operations conform to the standards expected by the pharmaceutical industry and health authorities. DF/HCC investigators are encouraged to contact the Core to discuss the potential for incorporating a pharmacokinetic substudy in the planning stages of new clinical trials under consideration.
- Development and validation of LC-MS/MS based analytical methods for the quantitative analysis of drugs and their metabolites in biological fluids and tissues
- Application of LC-MS/MS assays to the routine analysis of pharmacokinetic samples from clinical trials and nonclinical studies
- Comprehensive pharmacokinetic data analysis
As of the CCSG renewal, the core name has changed from "Cancer Pharmacology Core" to "Clinical Pharmacology Core".
Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children’s Oncology Group
Jeffery G. Supko, PhD (MGH)
This clinical trial evaluated whether the substitution of Erwinia asparaginase 25,000 IU/m2 for 6 doses given i.m. on a Monday/Wednesday/Friday (M/W/F) schedule to children with acute lymphoblastic leukemia and allergy to pegaspargase would provide a 48 h nadir serum asparaginase activity (NSAA) ≥0.10 IU/mL. A total of 1,045 serum samples from 58 patients were received by the Core for the determination of asparaginase activity using a validated biochemical assay. NSAA ≥0.10 IU/mL was achieved in 38 of 41 patients (92.7%) at 48 h and in 38 of 43 patients (88.4%) at 72 h after dosing during course 1. Among samples obtained during all courses, 95.8% (252 of 263) of 48 h samples and 84.5% (125 of 148) of 72 h samples had NSAA ≥0.10-IU/mL. Pharmacokinetic parameters were estimated for a total of 54 patients by fitting the serum asparaginase activity-time course for all 6 doses given during course 1 to a one-compartment open model with first-order absorption. The analysis served to identify the existence of two subpopulations of patients, each of which comprised approximately 50% of the total cohort, based upon the relative magnitude of the rate constants for the absorption and elimination of enzyme activity. In particular, there was a twofold difference in the mean apparent half-life of serum asparaginase activity between the two subgroups. It is likely that patient- specific factors, which remain to be identified, were responsible for influencing the rate of absorption of the enzyme from the i.m. injection site into systemic circulation, resulting in the observed differences in the pharmacokinetic behavior of asparaginase activity between the two subgroups. This study provided the basis for the FDA approval to use Erwinia asparaginase in patients with allergic reactions to pegaspargase.
Fig. (A) Correlation between the observed and model predicted asparaginase activity in 510 serum samples obtained from 54 patients during the initial course of therapy. The overall goodness of fit of the one-compartment open model with first-order absorption to the experimental data for individual patients is indicated by the closeness of the correlation coefficient (0.94) and slope of the best-fit line (0.86) to unity. (B) Mean serum asparaginase activity-time profile for the six 25,000-IU/m2 doses of IM Erwinia asparaginase given during the first course of therapy for 24 patients receiving the initial dose on a Wednesday. Data points are the geometric mean values of the observed asparaginase activity at each sample time shown together with 1-SD unit error bars. The continuous line is the best-fit curve determined by nonlinear regression analysis of the mean profile.
Contribution of the Core: Design of a sparse pharmacokinetic sampling schedule, the determination of asparaginase activity in serum samples received from a national multi-institutional clinical trial, and pharmacokinetic data analysis. A pharmacokinetic model that accurately described the time course of asparaginase activity in serum was identified and fit to the data for each patient.
Publication: Salzer WL, Asselin B, Supko JGMGH, Devidas M, Kaiser NA, Plourde P, Winick NJ, Reaman GH, Raetz E, Carroll WL, Hunger SP. Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children's Oncology Group. Blood, 2013; 25:507-14. PMC3724190
Phase I/II Study of Carboplatin and Pralatrexate in Patients with Recurrent Platinum Sensitive Ovarian, Fallopian Tube or Primary Peritoneal Cancer (DF/HCC 10-113)
Marcela del Carmen, MD (MGH)
In this phase 1 and 2 clinical trial, the appropriate dose of carboplatin-pralatrexate was identified in patients with recurrent, platinum-sensitive ovarian, fallopian tube, and primary peritoneal cancer. The regimen was well tolerated and most patients responded to treatment. Pharmacokinetic samples to define the time course of the pralatrexate concentration in plasma for the first dose given immediately after carboplatin on day 1 and the second dose when given alone on day 15 were obtained during cycle 1 The mean (±SD) total body clearance (20.9 ± 6.3 L/h) and biological half life (5.87 ± 2.00 h) of pralatrexate when given alone on day 15 at doses ranging from 30 to 105 mg/m2 were consistent with data reported for prior studies of single agent pralatrexate. Although prior studies found no change in the pharmacokinetics of pralatrexate upon repeated administration, we observed a significant reduction in the total body clearance of pralatrexate when given immediately after carboplatin as compared to the subsequent dose given alone 2 weeks later, suggestive of a drug interaction. The interaction appeared to be most pronounced in patients who received pralatrexate 105 mg/m2, the highest dose evaluated. Treatment-related toxicities after the initial dose of pralatrexate received in combination with carboplatin that required a reduction in the next dose of pralatrexate in cycle 1 occurred in 8 of 17 patients (47%) evaluated at this dose level.
Fig. Mean plasma concentration-time profiles in patients treated with 105 mg/m2 of pralatrexate. (A) Pralatrexate given immediately following the i.v. infusion of carboplatin on day 1 (circles) and alone on day 15 (squares) to 9 patients who received the same dose on both days. (B) Pralatrexate given after carboplatin on day 1 to 9 patients who received the full dose on day 15 (down triangles) and 8 patients who required a dose reduction on day 15 (up triangles). Data points are the geometric mean of the observed pralatrexate plasma concentration at each sample time with ±1-standard deviation unit error bars.
Contribution of the Core: Design of the pharmacokinetic sampling schedule, the development and validation of an LC-MS/MS assay for pralatrexate in human plasma, the routine analysis of pharmacokinetic samples, and pharmacokinetic data analysis.
Publication: Del Carmen MGMGH, Supko JGMGH, Horick NKMGH, Rauh-Hain JAMGH, Clark RMMGH, Campos SMDFCI, Krasner CN, MGH Atkinson TMGH, Birrer MJMGH. Phase 1 and 2 study of carboplatin and pralatrexate in patients with recurrent, platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer. Cancer, 2016;122:3297-3306. PMID: 27421044.
Timed Sequential Therapy of the Selective T-Type Calcium Channel Blocker Mibefradil and Temozolomide in Patients with Recurrent High-Grade Gliomas: A Phase 1b Adult Brain Tumor Consortium Study.
Jeffery G. Supko, PhD (MGH)
Mibefradil, previously approved as an antihypertensive therapy, has preclinical activity in glioblastomas with the ability to induce cell cycle arrest at G1/S. This phase 1 clinical trial was the first study undertaken to evaluate mibefradil as an anticancer therapy. The study was designed to determine the maximum tolerated dose of mibefradil when administered four times daily (QID) for 7 days followed by standard regimen temozolomide. The overall mean steady-state apparent oral clearance of mibefradil when given QID to brain cancer patients, 10.5 ± 2.8 L/h, was in excellent agreement with previously reported data for once daily (QD) dosing of the drug in healthy male subjects. The mean steady state maximum drug concentration in plasma achieved at the 75 mg QID dose level, 1,798 ± 540 ng/mL, was greater than 250 mg QD (1,506 ± 163 ng/mL), the highest dose for the QD schedule for which pharmacokinetic data has been reported. As expected, QID dosing resulted in a marked decrease in the steady state peak-to-trough ratio for the concentration of MIB in plasma as compared to QD dosing, from values ranging from 1.5-4.9 for QD dosing to only 1.16 ± 0.18 for QID dosing. Consequently, systemic exposure to near maximum concentrations of the drug is enhanced by QID dosing. The mean ratio of the area under the plasma concentration-time curve for the metabolite-to-parent drug for the final dose given on day 8 exhibited a dose-dependent trend, increasing from 1.04 ± 0.32 for the 25 mg QID dose to 2.27 ± 0.94 for 87.5 mg QID.
Fig. Mean plasma concentration-time profiles of mibefradil (solid circles) and its alcohol metabolite (solid squares) for the group of 6 patients receiving oral mibefradil 87.5 mg QID. Pharmacokinetic sampling was performed over single dosing intervals on day 2 after administration of the fourth consecutive dose, on day 5 after the sixteenth dose, and for 48 h after the final dose on day 8. The error bars represent 1 SD of the mean concentrations.
Contribution of the Core: Design of the pharmacokinetic sampling schedule, the development and validation of an LC-MS/MS assay for mibefradil and its alcohol metabolite in human plasma, the routine analysis of pharmacokinetic samples, and pharmacokinetic data analysis.
Publication: Holdhoff M, Ye X, Supko JGMGH, Nabors LB, Desai AS, Walbert T, Lesser GJ, Read WL, Lieberman FS, Lodge MA, Leal J, Fisher JD, Desideri S, Grossman SA, Wahl RL, Schiff D. Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas: a phase 1b Adult Brain Tumor Consortium study. Neuro Oncol, 2017; Mar 22 [Epub ahead of print]. PMID: 28371832
For more information or to contact the Clinical Pharmacology Core, visit the core website here.