Influence of Concomitant Administrations on the Clearance of Theophylline as Analyzed by Population Pharmacokinetics

Selecting the optimum dose of theophylline is difficult because of the complication of pharmacokinetics caused by inter-individual variability and the effects of coadministration with other drugs.The steady-state serum concentration of theophylline (n=221) following repetitive oral administration in 174 hospitalized patients was analyzed using NONMEM. Analysis of the pharmacokinetics of theophylline was accomplished with a simple steady-state pharmacokinetic model. The effects of a variety of developmental and demographic factors on the clearance of theophylline were investigated. The clearance of theophylline was significantly influenced by the demographic variables of age, and co-administration with ciprofloxacine or allopurinol. Estimates obtained by NONMEM indicated that the clearance of theophylline in patients under 16 years old was 128% higher than that in those over 16 years old.Concomitant administration of ciprofloxacine or allopurinol decreased the clearance of theophylline by 56.3% and 69.4%, respectively.The final regression model of relative clearance of theophylline was: CL (ml/kg/h) =40.5ξ×5ξ×6ξ×7where ξ5=0.563 for co-administration of ciprofloxacine, ξ6=0.694 for co-administration of allopurinol, ξ7=1.28 for patients younger than 16 years old.This technique can be used to estimate the pharmacokinetic parameters of a population from sparse data collected during routine clinical care and to determine the extent of drug interaction.