title: Population pharmacokinetics of high-dose methotrexate after intravenous administration in Chinese osteosarcoma patients from a single institution.
abstract: 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/m 2 ) 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 ) = CL1TV × [1 - θ CL1- MTXNUM × MTXNUM] × [1 - θ CL1- CrCl1 × (CrCl1 - 1.89)] × e ηCL1i (L/h). V1 (central volume): (V1)i = V1TV × e ηV1i (L). CL2 (clearance of peripheral compartment): (CL2)i = CL2TV × [1 - θCL2 - BODY AREA × (body area - 1.62)] × e ηCL2i (L/h). V2 (peripheral compartment): (V2 )i = V2TV × [1 - θ V2-bodyarea × (bodyarea-1.62)] × e ηV2i (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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xiaohuang
authors.initials: X
authors.lastname: Tian
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Clinical Pharmacology, Beijing Jishuitan Hospital, Beijing 100035, China.
authors.forename: Jiancun
authors.initials: J
authors.lastname: Zhen
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Niu
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use*; D008958:Models, Molecular; D012516:Osteosarcoma / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D002955:Leucovorin; D008727:Methotrexate