Population pharmacokinetics of theophylline. I: Intravenous infusion to children in the acute episode of asthma

The population pharmacokinetics of theophylline during constant-rate intravenous infusion has been studied in 66 children (8.7±4.7 year of age; 26.0±12.8kg, mean±S.D.) with an episode of acute asthma. One hundred and twelve theophylline serum concentrations (13.9±4.8μg/mi) collected retrospectively were analyzed using a nonlinear mixed-effect model. The influence of hepatic dysfunction, age, gender, days after admission, blood gas measurements (PaO₂, PaCO₂, blood pH) and clinical analyses data (total serum protein, albumin concentration, haemoglobin concentration, haematocrit) on theophylline clearance was examined by the likelihood ratio test. A final estimate of population mean clearance was 58.6ml/kg/h, which was decreased by 36% in patients with hepatic dysfunction. Other factors tested displayed no statistically significant effect on theophylline clearance. The inter-individual variability in clearance was 26% while the intra-individual variability in theophylline concentrations was 2.6μg/ml as a standard deviation, which was almost double that observed for stable patients. Taking into account that the therapeutic window of this drug is 10—20μg/ml, this value indicates a relatively large intra-individual variability and suggests that frequent (daily)monitoring of serum concentrations is necessary for patients with an episode of acute asthma.