Bayesian estimation of methotrexate pharmacokinetic parameters and area under the curve in children and young adults with localised osteosarcoma.

BACKGROUND: Methotrexate is the most efficient anticancer drug in osteosarcoma. It requires individual exposure monitoring because of the high doses used, its wide interpatient pharmacokinetic variability and the existence of demonstrated relationships between efficacy, toxicity and serum drug concentrations. OBJECTIVE: To develop a maximum a posteriori (MAP) Bayesian estimator able to predict individual pharmacokinetic parameters and exposure indices such as area under the curve (AUC) for methotrexate from a few blood samples, in order to prevent toxicity and facilitate further studies of the relationships between efficacy and exposure. METHODS: Methotrexate population pharmacokinetics were estimated by a retrospective analysis of concentration data from 40 children and young adults by using the nonparametric expectation maximisation method NPEM. A linear two-compartment model with elimination from the central compartment was assumed. Individual pharmacokinetic parameters and AUC were subsequently estimated in 30 other young patients, using MAP Bayesian estimation as implemented in two programs, ADAPT II and an inhouse program Winphar((R)). RESULTS: The pharmacokinetic parameters used in the model were the volume of the central compartment (V(1)) and the transfer constants (k(10), k(12) and k(21)). The mean values (with percentage coefficient of variation) obtained were: 18.24L (54.1%) and 0.41 (42.3%), 0.0168 (68.7%), and 0.1069 (61.3%) h(-1), respectively. Bayesian forecasting enabled nonbiased estimation of AUC and systemic clearance using a schedule with two sampling times (6 and 24 hours after the beginning of the infusion) and either program. Collection of a third sample at 4 hours improved the precision. CONCLUSION: The Bayesian adaptive method developed herein allows accurate estimation of individual exposure to methotrexate and can easily be used in clinical practice.

[Progress and stagnation in chemotherapy protocols for primary osteosarcoma]. / Progrès et stagnation dans la chimiothérapie des ostéosarcomes primitifs.

Thirty years ago, osteosarcoma of a limb meant amputation and death. Two years after diagnosis, 80% of the patients died from pulmonary metastases, despite early amputation. In 2002, more than 70% of these patients can be cured. Successful cure requires adequate and early management centered on en-bloc resection by a specialized surgeon, followed by a long, expensive, and adapted chemotherapy. The cornerstone is high-dose methotrexate. We present data accumulated over the last 30 years on the treatment of osteosarcoma and point out the fundamental steps of this success story.