Population pharmacokinetics of high-dose methotrexate in osteosarcoma pediatric patients.

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Introduction and Objectives: High-dose methotrexate (HD_MTX) is an efficient component of therapy in children with osteosarcoma. The aim of this study was to establish the population pharmacokinetics of HD-MTX in children with osteosarcoma and explore the influence of patient covariates and interoccasion variability on drug disposition.

Methods: Fourteen children (nine males and five females) treated in the “Hospital de la Santa Creu i Sant Pau” were eligible for this study. The demographic and biochemical data (age weight, height, body surface area, serum creatinine and creatinine clearance: CRCL) were recorded from the patient files. Patients received sixteen courses of MTX over a 4 hour intravenous infusion (mean dose, 11.19 g/m²) according to the Spanish Oncology Society guidelines.Blood samples were collected at 1,2,4,24,36 and 48 hr. after the start of infusion. Pharmacokinetic (PK) analysis was performed using the population approach by means of NONMEM V.

Results : According to previous data (1), the pharmacokinetics of MTX was best described by a two compartment open PK model with elimination from the central compartment. PK parameter variability was modelled as log-normally distributed. Intersubject variability (ISV) was included in total plasma clearance (10.3%) and in central compartment distribution volume (47.7%). Interoccasion variability (IOV) was only retained for CL (13.1%). Residual variability consisted of a proportional error of 53.1%.. A covariate model based on creatinine clearance was identified as appropriate model to describe part of the variability in MTX clearance. The final estimates of fixed effect parameters (CL,total plasma clearance;V₁ and V₂, volumes of distribution of the central, and peripheral compartments, respectively; CL_D1 intercompartmental clearance), were CL=55.5+52.2*(CRCL/134.83) L/day, 24.8 L and 1.23 L and 0.319 L/day, respectively.

Conclusion: A population PK model for MTX has been developed. It incorporates measure of renal function to predict total drug clearance. Validation of this model with external patients should be performed in order to assess the suitability of further MTX therapeutic drug monitoring.

References:
1.Rousseau et al. Clin.Pharmacokinet. 2002,41(13):1095-1104.