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Predictors of and variability in methotrexate clearance among osteosarcoma patients receiving high-dose therapy

Pinchasik, Dawn

Abstract Details

2013, MS, University of Cincinnati, Medicine: Clinical and Translational Research.
BACKGROUND: Osteosarcoma is the most common primary malignancy of bone in children and adults. High-dose Methotrexate (MTX) is an important component of osteosarcoma therapy, but is associated with toxicity. Patients demonstrate wide variability in MTX pharmacokinetics and may not clear the drug in the time expected. Exposure has been correlated with clinical outcome and toxicity in previous studies. The purpose of this study is to 1) utilize a population model-based method to estimate MTX clearance and exposure and 2) to evaluate a variety of covariates as potential predictors of delayed MTX clearance. MATERIALS AND METHODS: A population model was used to estimate MTX pharmacokinetics for 19 children and young adults who were treated for osteosarcoma. Anthropometric measures, co-morbidities, concurrent medications, and parameters of organ function were reviewed retrospectively and assessed as possible predictors of delayed MTX clearance. Patients were deemed to have delayed clearance if the plasma MTX concentration exceeded the target level for that time point, based on the protocol being followed. In addition, the accuracy of pharmacokinetic estimates generated in the absence of peak (4-hour) MTX concentration was assessed. RESULTS: MTX clearance was delayed in 9 of 19 patients, following their first ever infusion of high-dose MTX. GFR was found to be a significant (P=0.0142) predictor of delayed clearance, as indicated by a plasma MTX concentration >0.1 µmol/L at hour 72 from the start of infusion. Pharmacokinetic parameters generated without consideration of the peak MTX concentration led to overestimation of clearance (P=0.0003) and underestimation of exposure (P=0.0001). CONCLUSIONS: Delayed clearance of MTX is common, during treatment for osteosarcoma, and may be predicted based on GFR. Pharmacokinetic estimates generated in the absence of a peak plasma MTX level, obtained at the end of the infusion, do not accurately represent clearance or exposure, following high-dose MTX administration.
Erin Nicole Haynes, Dr.P.H. (Committee Chair)
Maureen O'Brien, Ph.D. (Committee Member)
Alexander Vinks, Pharm.D., Ph.D. (Committee Member)
24 p.

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Citations

  • Pinchasik, D. (2013). Predictors of and variability in methotrexate clearance among osteosarcoma patients receiving high-dose therapy [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377870526

    APA Style (7th edition)

  • Pinchasik, Dawn. Predictors of and variability in methotrexate clearance among osteosarcoma patients receiving high-dose therapy. 2013. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377870526.

    MLA Style (8th edition)

  • Pinchasik, Dawn. "Predictors of and variability in methotrexate clearance among osteosarcoma patients receiving high-dose therapy." Master's thesis, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377870526

    Chicago Manual of Style (17th edition)