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Alterations in theophylline metabolism during the first year of life
D M Kraus1, J H Fischer, S J Reitz
1Department of Pharmacy Practice, University of Illinois at Chicago 60612.
Insights
Postconceptional age, not postnatal age, is the key factor for theophylline metabolism maturation in infants. This finding is crucial for optimizing theophylline therapy and ensuring infant safety during treatment.
Area of Science:
- Pharmacology
- Neonatal Medicine
- Clinical Pharmacy
Background:
- Theophylline is commonly used for respiratory conditions in infants.
- Understanding theophylline disposition is vital for safe and effective therapeutic drug monitoring.
- Infant maturation significantly impacts drug metabolism and clearance.
Purpose of the Study:
- To evaluate maturational changes in theophylline disposition in infants.
- To identify the primary clinical parameter influencing these maturational changes.
- To determine the optimal maturational marker for guiding theophylline therapy in neonates and infants.
Main Methods:
- Studied 52 infants receiving maintenance theophylline therapy.
- Measured theophylline and metabolites in serum and urine at steady state.
- Utilized multiple stepwise linear regression to analyze the influence of clinical parameters.
Main Results:
- Theophylline clearance and metabolite patterns normalized to adult levels by 55 weeks postconceptional age.
- Postconceptional age was the strongest predictor of theophylline clearance and metabolite excretion.
- Development of the demethylation pathway to 3-methylxanthine correlated with improved theophylline clearance.
Conclusions:
- Postconceptional age is a more accurate maturational marker than postnatal age for theophylline therapy in infants.
- This finding aids in refining dosing strategies and improving therapeutic outcomes.
- Accurate maturational assessment is essential for managing theophylline in the neonatal population.
Abstract:
Maturational changes in theophylline disposition were evaluated in 52 infants (gestational age, 24 to 40 weeks; postnatal age, 2 to 69 weeks) receiving maintenance theophylline therapy. Theophylline and metabolites were measured in serum and urine at steady state, and the influence of clinical parameters on the maturational changes was analyzed by multiple stepwise linear regression. Theophylline clearance and urine metabolite pattern reached adult values at 55 weeks' postconceptional age. Serum caffeine concentrations greater than 1 microgram/ml occurred in infants up to 50 weeks' postconceptional age. Disappearance of serum caffeine concentrations and maturation of theophylline clearance were primarily related (p < 0.001) to development of the demethylation pathway to 3-methylxanthine. Postconceptional age was the major factor (p < 0.001) explaining the interpatient variability in theophylline clearance (r2 = 0.57), serum caffeine to theophylline ratio (r2 = 0.46), and urinary excretion of theophylline (r2 = 0.51), caffeine (r2 = 0.49), 1,3-methyluric acid (r2 = 0.32), 1-methyluric acid (r2 = 0.53), and 3-methylxanthine (r2 = 0.58). Our findings indicate that postconceptional age rather than postnatal age should be used as a maturational marker during theophylline therapy in infancy.