Therapeutic Drug Monitoring of High Dose Methotrexate in Osteosarcoma Patients

Abstract

Introduction: Methotrexate (MTX), a folic acid antagonist, is used widely for treatment of various types of cancer. In treatment of osteosarcoma by high dose methotrexate (HDMTX), therapeutic drug monitoring (TDM) is usually performed for improving the efficacy and prevention of adverse drug reactions. Pharmacokinetic profile of MTX is useful for improving the TDM protocol for HDMTX. The objectives were to study pharmacokinetic parameters of HDMTX and design the TDM of HDMTX protocol.  Materials and Method: A retrospective study evaluated data from TDM of HDMTX in patients with osteosarcoma during July 2012 to June 2013.  The pharmacokinetic parameters (elimination rate constant; k_e, and terminal half-life; T_1/2) were calculated from serum MTX concentrations at various times, then the appropriate sampling time for TDM according to the pharmacokinetic profile of HDMTX was determined. Results: The data of serum concentration at various times after the end of 24-hr infusion of HDMTX (70 cycles from 26 patients) were examined. Patients in this study were 17 to 49 year-old (21.27±7.59 year-old), and all of them has the glomerular filtration rate over 80 mL/min/1.73m². At 72 hr after the end of infusion, 64.28% of patients revealed predicted MTX concentrations lower than 0.2 µM. The average calculated k_e and T_1/2 were 0.048 ± 0.0190 hr^-1 and 16.24 ± 6.11 hr, respectively. Conclusion: The appropriate sampling time for TDM of HDMTX in treatment of osteosarcoma is at 72 hr after the end of 24 hr infusion, then every 24 hr until the concentration below 0.1 µM. Further study of the relationship between regimen of leucovorin rescue to the efficacy and toxicity of HDMTX should be performed.