Population Pharmacokinetics Of Osteosarcoma Patiants Used High-dose Methotrexate

Background and Objective:High-dose methotrexate (MTX) chemotherapy had been used for osteosarcomaby Jafe since1972,it had a large number of clinical studies during decades,whichmade it rational using of increasingly sophisticated,but there is very different indose of pationts and in individual patient,so does it still has serious adverse reactions,sometime even fatal action.Contemporary medicine for cancer treatment proposedindividualized drug therapy.How to make osteosarcoma patients the acceptance of thetherapy got best benefits and minimize toxicity, which requires more innovativeextensive, more and in-depth research methods than ever.In this paper, we designed apopulation pharmacokinetic study in osteosarcoma patients used high-dosemethotrexate in order to obtain population pharmacokinetic parameters and assess age,sex, weight, alanine aminotransferase (ALT), aspartate aminotransferase (AST),serum creatinine (SCR) on the pharmacokinetic parameters.The drug concentrationsof individual patient can be predicted according to the model have been developedand Bayesian method,which provides individualized treatment services.Methods：In this study, the relevant clinical data in our hospital of58osteosarcoma patientsreceived high-dose methotrexate chemotherapy from January2009to December2013is collected, including26females,32males. A pharmacokinetic model was developedusing nonlinear mixed-effect model （NONMEM）software——kinetica（version4.4）， the influences of age, sex, weight, alanine aminotransferase (ALT), aspartateaminotransferase(AST), serum creatinine(SCR) in population pharmacokinetic modeland parameters were investigated.Results：The pharmacokinetics of high dose methotrexate were described by atwo-compartment model. Metabolic process of high-dose methotrexate after24hours accord the elimination of one-compartment model, the Kinetica soft analysis plasmaconcentrations， the volume after24hours (V)0.0597986L， elimination rateconstant(Kel)0.132738, Serum creatinine correlate with elimination rate constant,theequation for the covariates: Kel=0.198236-CREA*0.000665374.Conlusion：1.In this study，the NONMEM (Kinetica software) conduct the populationpharmacokinetic study in osteosarcoma patients used high-dose MTX, estimatedpharmacokinetic parameters of this study embodied the basic characteristics of thisgroup.2.This study found that serum creatinine had a significant effect on the clearancerate.it should be taken seriously, to avoid or reduce the incidence of toxicity.3.Kinectica software can predict the pations’ MTX plasma concentration basedon clinical data of theirs，which could give helps for designing individualized plan ofMTX treatment and reducing drug toxicity.