Population Pharmacokinetics of High-dose Methotrexate After Intravenous Administration in Chinese Osteosarcoma Patients from a Single Institution

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, x [1-theta(CL1-MTXNUM) x MTXNUM] x [1-theta(CL1-CrCl1) x (CrCl1-1.89)] x e(eta cl gamma) (L/h) . VI (central volume): (V-1)(i) = V(1TV)xe(eta 1 gamma) (L) . CL2 (clearance of peripheral compartment): (CL2)(i) = CL2TV x [1-theta(CL2-BODYAREA) x (bodyarea - 1.62)] x e(eta cl gamma) (L/h) . V2 (peripheral compartment): (V-2)(i) = V-2TV x [1-theta(v2-bodyarea) X (bodyarea-1.62)] x e(eta gamma 2l) (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.