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Plasma levels after oral methotrexate in children with juvenile rheumatoid arthritis
A Ravelli1, G Di Fuccia, M Molinaro
1Clinica Pediatrica dell'Università, Dipartimento di Farmacologia, IRCCS S. Matteo, Pavia, Italy.
Abstract:
Plasma levels of methotrexate (MTX) after oral administration of 6.4 to 11.2 mg/m2/week (mean 8.5 mg/m2/week) were studied in 33 children with severe juvenile rheumatoid arthritis (JRA). MTX concentrations were measured by a fluorescence polarization immunoassay (TDx) at 1, 2, 3, and 24 h after administration. The maximum level was observed in most patients after 1 h. No significant correlation was found between MTX dosage and the 1, 2, and 3-h plasma levels. No patient showed values in the range of probable toxicity 24 h after administration. A stepwise multiple regression analysis on 1, 2, and 3-h MTX levels, selected clinical features, dosage and duration of MTX therapy, and concomitant drug treatment showed that MTX concentrations at the different time points tend to be closely related; among the other variables, only concurrent treatment with salicylates was found to affect significantly the 3-h level. Serial determinations performed in 20 patients at the same oral dosage showed a wide interindividual and intraindividual variability of the plasma levels from the first dose to the next. Variable and unpredictable levels were observed also in most of the 8 patients studied after one or more increases of MTX dosage. No difference in MTX concentrations was observed between patients who responded to treatment and those who failed to respond, and between patients who had serum transaminase elevation and those who did not. Our results suggest that, until the pharmacokinetics of low dose MTX is clarified, routine therapeutic monitoring of MTX has a limited value in the clinical management of children with JRA.
Insights
Plasma levels of methotrexate (MTX) in children with juvenile rheumatoid arthritis (JRA) showed significant variability. Routine therapeutic drug monitoring of MTX has limited clinical value due to unpredictable levels.
Area of Science:
- Pediatric Rheumatology
- Pharmacokinetics
- Clinical Pharmacology
Background:
- Juvenile rheumatoid arthritis (JRA) is a chronic autoimmune disease affecting children.
- Methotrexate (MTX) is a common disease-modifying antirheumatic drug (DMARD) used in JRA treatment.
- Understanding MTX pharmacokinetics is crucial for optimizing treatment efficacy and safety.
Purpose of the Study:
- To investigate plasma methotrexate (MTX) levels in children with severe JRA.
- To assess the correlation between MTX dosage, plasma concentrations, and clinical outcomes.
- To evaluate the utility of routine therapeutic drug monitoring for MTX in JRA.
Main Methods:
- 33 children with JRA received oral MTX (6.4-11.2 mg/m2/week).
- Plasma MTX concentrations were measured using fluorescence polarization immunoassay at 1, 2, 3, and 24 hours post-administration.
- Statistical analyses, including stepwise multiple regression, were used to identify factors influencing MTX levels.
Main Results:
- Maximum MTX plasma levels were typically observed at 1 hour.
- No significant correlation was found between MTX dosage and early plasma levels (1-3 hours).
- Significant inter- and intra-individual variability in MTX plasma levels was observed, even at stable dosages.
- Concurrent salicylate use was the only factor significantly affecting 3-hour MTX levels.
- No association was found between MTX levels and treatment response or adverse effects (transaminase elevation).
Conclusions:
- Low-dose oral MTX pharmacokinetics in children with JRA are variable and unpredictable.
- Routine therapeutic drug monitoring of MTX plasma levels currently offers limited value in managing JRA.
- Further research is needed to clarify MTX pharmacokinetics for improved clinical management in pediatric patients.