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Developmental pharmacogenetics in pediatric rheumatology: utilizing a new paradigm to effectively treat patients with juvenile idiopathic arthritis with methotrexate.

ABSTRACT: Although methotrexate is widely used in clinical practice there remains significant lack of understanding of its mechanisms of action and the factors that contribute to the variability in toxicity and response seen clinically. In addition to differences in drug administration, factors that affect pharmacokinetics and pharmacodynamics such as genetic variation may explain individual differences in drug biotransformation. However, the pediatric population has an additional factor to consider, namely the ontogeny of gene expression which may result in variation throughout growth and development. We review the current understanding of methotrexate biotransformation and the concept of ontogeny, with further discussion of how to implement a developmental pharmacogenomics approach in future studies.

SUBMITTER: Becker ML

PROVIDER: S-EPMC2958653 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Developmental pharmacogenetics in pediatric rheumatology: utilizing a new paradigm to effectively treat patients with juvenile idiopathic arthritis with methotrexate.

Becker Mara L ML Leeder J Steven JS

Human genomics and proteomics : HGP 20100622

Although methotrexate is widely used in clinical practice there remains significant lack of understanding of its mechanisms of action and the factors that contribute to the variability in toxicity and response seen clinically. In addition to differences in drug administration, factors that affect pharmacokinetics and pharmacodynamics such as genetic variation may explain individual differences in drug biotransformation. However, the pediatric population has an additional factor to consider, name ...[more]

PMID: 20981233

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Project description:BACKGROUND: Methotrexate (MTX) is an effective and safe drug in the treatment of juvenile idiopathic arthritis (JIA). Despite its safety, MTX-related gastrointestinal adverse effects before and after MTX administration, termed MTX intolerance, occur frequently, leading to non-compliance and potentially premature MTX termination. The aim of this study was to construct a risk model to predict MTX intolerance. METHODS: In a prospective JIA cohort, clinical variables and single nucleotide polymorphisms were determined at MTX start. The Methotrexate Intolerance Severity Score was employed to measure MTX intolerance in the first year of treatment. MTX intolerance was most prevalent at 6 or 12 months after MTX start, which was defined as the outcome for the prediction model. The model was developed in 152 patients using multivariable logistic regression analysis and subsequently internally validated using bootstrapping. RESULTS: The prediction model included the following predictors: JIA category, antinuclear antibody, parent/patient assessment of pain, Juvenile Arthritis Disease Activity Score-27, thrombocytes, alanine aminotransferase and creatinine. The model classified 77.5% of patients correctly, and 66.7% of patients after internal validation by bootstrapping. The lowest predicted risk of MTX intolerance was 18.9% and the highest predicted risk was 85.9%. The prediction model was transformed into a risk score (range 0-17). At a cut-off of ?6, sensitivity was 82.0%, specificity 56.1%, positive predictive value was 58.7% and negative predictive value 80.4%. CONCLUSIONS: This clinical prediction model showed moderate predictive power to detect MTX intolerance. To develop into a clinically usable tool, it should be validated in an independent cohort and updated with new predictors. Such an easy-to-use tool could then assist clinicians in identifying patients at risk to develop MTX intolerance, and in turn to monitor them closely and intervene timely in order to prevent the development of MTX intolerance. TRIAL REGISTRATION: ISRCTN register, www.isrctn.com, ISRCTN13524271.

Dataset Information

Developmental pharmacogenetics in pediatric rheumatology: utilizing a new paradigm to effectively treat patients with juvenile idiopathic arthritis with methotrexate.

Publications

Developmental pharmacogenetics in pediatric rheumatology: utilizing a new paradigm to effectively treat patients with juvenile idiopathic arthritis with methotrexate.

Similar Datasets

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