Document Detail


Bayesian estimation of methotrexate pharmacokinetic parameters and area under the curve in children and young adults with localised osteosarcoma.
MedLine Citation:
PMID:  12403645     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Annick Rousseau; Christophe Sabot; Nicole Delepine; Gerard Delepine; Jean Debord; Gerard Lachâtre; Pierre Marquet
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Publication Detail:
Type:  Clinical Trial; Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical pharmacokinetics     Volume:  41     ISSN:  0312-5963     ISO Abbreviation:  Clin Pharmacokinet     Publication Date:  2002  
Date Detail:
Created Date:  2002-10-29     Completed Date:  2003-04-09     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7606849     Medline TA:  Clin Pharmacokinet     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  1095-104     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Toxicology, University Hospital, Limoges, France. rousseau@pharm.unilim.fr
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Antimetabolites, Antineoplastic / blood,  pharmacokinetics*,  therapeutic use
Area Under Curve
Bayes Theorem
Child
Child, Preschool
Dose-Response Relationship, Drug
Humans
Linear Models
Methotrexate / blood,  pharmacokinetics*,  therapeutic use
Models, Biological
Osteosarcoma / drug therapy,  metabolism*
Retrospective Studies
Software
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 59-05-2/Methotrexate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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