Dose-dependent kinetics of theophylline disposition in asthmatic children

Prior assumptions of first-order elimination for theophylline were tested by administering theophylline by intravenous infusion at two dosage levels to 20 children with chronic asthma. The resulting steady-state serum concentrations increased to a greater degree than would have been predicted if increases in serum concentration were proportional to changes in dose, and the subsequent calculation of clearance revealed values of 1.37 +/- 0.09 ml/kg/minute (mean +/- SE of the mean) at the lower infusion rate and of 1.21 +/- 0.06 ml/kg/minute at the higher infusion rate (p less than 0.02). Even greater differences in clearance were present among ten of these children whose higher infusion rates were at least two times greater than the lower rate. An additional child was observed who experienced a seizure following a medication error that resulted in a 50% increase in daily dosage and a greater than threefold increase of serum concentration. The nonlinear nature of the relationship between dose and serum concentration suggests that theophylline dosage adjustment should be performed cautiously using small increments.