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 +/- 12.8 kg, mean +/- S.D.) with an episode of acute asthma. One hundred and twelve theophylline serum concentrations (13.9 +/- 4.8 micrograms/ml) 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 58.6 ml/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 2.6 micrograms/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 10-20 micrograms/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.