POPULATION PHARMACOKINETICS OF THEOPHYLLINE .2. INTRAVENOUS-INFUSION TO PATIENTS WITH STABLE CHRONIC AIRWAY-OBSTRUCTION

The population pharmacokinetics of theophylline were studied in 55 pat ients with stable chronic airway obstruction. Two hundred and seventy six theophylline serum concentrations after intravenous short infusion were analyzed using a nonlinear mixed-effect model. The influence of hepatic dysfunction, smoking habit, age and the measurement of arteria l blood gases (oxygen tension: PaO2, carbon dioxide tension: PaCO2, bl ood pH) and clinical laboratory tests (serum albumin concentration, ha ematocrit) on the pharmacokinetic parameters of theophylline was exami ned by the likelihood ratio test. Assessment of each factor was made b y a forward selection method. In the final regression model, the total body clearance (CL, l/h/kg) was related to the value of PaCO2 as well as to the presence of hepatic dysfunction, and the volume of distribu tion (V(d), l/kg) was related with the PaCO2 value as expressed in the following equations: CL = exp(-3.78-0.525.HF+0.0233.PaCO2) and V(d) = exp(-1.12+0.00934.PaCO2), where HF is a categorical variable with a v alue of unity if a patient has hepatic dysfunction otherwise zero. The interactions among blood gas measurements were observed and the CL an d V(d) of theophylline would be inversely correlated with PaO2 or pH, if we selected PaO2 or blood pH to be a more important factor than PaC O2. The inter-individual variabilities in CL and V(d) were 38.5% and 1 2.5%, respectively, and the residual variability in theophylline serum concentrations was 10.6% as a coefficient of variation. This final mo del and the population parameters of theophylline will be useful for i ndividualization of a drug dosage regimen by means of the Bayesian met hod. Significant correlation between arterial blood gas measurements a nd pharmacokinetic parameters observed in this study indicates that th e pharmacokinetics of theophylline can vary in association with the se verity of respiratory diseases.