STEADY-STATE POPULATION PHARMACOKINETICS OF SUSTAINED-RELEASE THEOPHYLLINE IN ADULT ASTHMATIC-PATIENTS

The steady-state population pharmacokinetics of theophylline were studied in 52 asthmatic adult patients who received sustained-release theophylline as armophylline or euphylline. A total of 92 steady-state plasma theophylline concentration-dosage pairs were analyzed using a nonlinear mixed effects model. The pharmacokinetic model used was a one-compartment open model with single path Michaelis-Menten elimination. Dosage was adjusted to body weight. The effects of age, gender, alcohol consumption, cigarette smoking, dosage form, concurrent treatment with beta-agonists or steroids, outpatient dosing, and plasma caffeine concentration on maximum elimination rate (V(m)) and Michaelis constant for theophylline metabolism (K(m)) were investigated. Hypothesis testing produced a final model in which K(m) = 0.42 (mg/l), and V(m) (mg/kg per day) was based on cigarette smoking and dosage form, with V(m) = 7.54 + 2.01 (smoking) + 1.08 (euphylline). Estimated coefficients of variation for interindividual variability in K(m) and V(m) were 162.6% and 48.1%, respectively. Residual variability in dosage rates was estimated as 0.90 mg/kg per day. The identification of factors influencing theophylline disposition should prove useful for the a priori design of theophylline dosage regimens and monitoring of drug levels during therapy.