Background:High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is the gold standard therapy in the treatment of osteosarcoma. The plasma concentration of MTX is closely related to efficacy and toxicity. There are large individual differences. Many authors have described the pharmacokinetic (PK) profile of MTX regarding osteosarcoma under a variety of circumstances. However, no data concerning Chinese osteosarcoma patient PKs using the nonlinear mixed effects models (NONMEM) have been previously reported. The goals of this study were to establish the population pharmacokinetics (PPK) of HD-MTX treatment in Chinese osteosarcoma patients, and to explore the influence of patient covariates and between-occasion variability on drug disposition.Methods:An intravenous HD-MTX solution (10 g/m2) was given 274 times to 148 osteosarcoma patients. MTX plasma concentrations were measured at 0, 6, 12, 24, 48 and 72 h after commencement of the infusion, and the fluorescence polarization immunoassay was used to determine MTX plasma concentrations. The PPK model and parameters were estimated using NONMEM software. The effects of fixed-effect factors were evaluated, and the final regression model was obtained.Results:The following population parameters were obtained using a two-compartment model: CL1 (clearance of central compartment):(CL1)i = CL1TV × [1- θCL1 −MTXNUM × MTXNUM]×[1-θCL1 −CrCI1 × (CrCl1 −1.89)]×eηCL1i (L/h). V1 (central volume):(V1)i = V1TV × eηV1i (L). CL2 (clearance of peripheral compartment):(CL2)i = CL2TV ×[1- θCL2 −BODYAREA × (bodyarea − 1.62)]×eηCL2i (L/h). V2(peripheral compartment):(V2)i = V2TV ×[1 − θV2−bodyarea × (bodyarea-1.62)]× eηV2i (L). The PPK parameters (RSD%) were CL1, V1, CL2 and V2 with values of 6.20 L/h (8.48%), 19.6 L (extremely small), 0.0172 L/h (50.9%) and 0.515 L (39.1%), respectively. Creatinine clearance and the number of methotrexate chemotherapy cycles before MTX infusion had a significant effect on the CL1, and body surface area had a significant effect on the CL2 and the V2 (P < 0. 01).Conclusions:A good fit was derived for the PPK. The model could be used to provide guidance for MTX treatment and reduce adverse effects.

The authors confirm that the PI for this paper is Rongsheng Zhao and that he had direct clinical responsibility for patients included in the study investigating the patients' willingness on individualized medication of high-dose methotrexate.

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Background:High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is “gold standard” therapy for osteosarcoma. Plasma concentrations of methotrexate (MTX) are closely related to its efficacy and toxicity. Delayed excretion of MTX can lead to serious adverse reactions that may result in treatment cessation, irreversible organ damage, and death. This study focused on the incidence of delayed excretion of MTX in Chinese osteosarcoma patients.Methods:A total of 1277 osteosarcoma patients were treated with HD-MTX chemotherapy (4291 cycles) from 2010 to 2015. Factors that could influence delayed excretion of MTX (gender, age, number of chemotherapy cycles, and serum concentration of MTX) were analyzed.Results:The incidence of delayed excretion of MTX (serum concentrations at 24 h [C24 h] >5 μmol/L) and severe delayed excretion of MTX (C24 h >20 μmol/L) were 6.19% and 0.86% per patient, and 2.31% and 0.26% per cycle of treatment, respectively. The incidence of severe delayed excretion of MTX was associated with gender, age, and C24 h.Conclusions:Precaution of delayed excretion of MTX is needed during osteosarcoma treatment using HD-MTX. An optimal individualized rescue strategy can be created with consideration of gender, age, and C24 h.