Intraindividual variability in theophylline pharmacokinetics in subjects with mild/moderate asthma

Intrasubject variability in theophylline pharmacokinetics was assessed in six subjects with mild/moderate asthma. On four occasions, each separated by a minimum of 3 weeks, a 6 mg/kg intravenous aminophylline dose was infused during 30 minutes, and multiple blood samples were obtained thereafter. The pharmacokinetic parameters of clearance (Cl), volume of distribution, and half-life were determined by noncompartmental analysis. There was evidence for within-subject variability in these parameters. In comparison to the first study day, Cl changed by greater than 15% in all but one subject and by greater than 25% in two of six subjects. Changes in half-life exceeding 25% of the value observed on the first study day occurred in three of six subjects. Within-subject coefficient of variation for Cl was 14.9% (range 3.9% to 33.3%) and 14.4% (range 5.8% to 24.3%) for half-life. Volume of distribution, however, was a more stable parameter with a within-subject coefficient of variation of 7.2% (range 2.3% to 11.1%). Thus, within-subject changes in the pharmacokinetics of theophylline do exist over time. These data suggest that close monitoring of patients receiving theophylline is warranted, particularly when theophylline concentrations are maintained at either extreme of the therapeutic range.