Evaluation of the effect of nonlinear kinetics on dosage adjustments of theophylline

The pharmacokinetics of theophylline at two different dosage levels were studied in six adult volunteers. The subjects were allowed to reach steady-state serum concentrations of theophylline after 7 days of administration of a sustained-release oral product. There was a statistically significant decrease (p = 0.03) in the total body clearance (TBC) of theophylline at the higher dosage level. At a daily dose of 10.6 mg/kg/day, the mean TBC was 0.76 ml/min/kg, whereas at a dose of 15.7 mg/kg/day the TBC averaged 0.68 ml/min/kg. For two of the subjects, a linear increase in serum concentrations occurred with increasing doses. The remaining four subjects showed a saturation of the elimination processes at the higher dosage. The apparent maximum velocity (Vmax) calculated in these subjects averaged 2,923 mg/day. The mean Michaelis-Menten constant (Km) was 23.70 micrograms/ml. Computer-generated serum concentrations produced by a linear increase in doses predicted toxic concentrations of theophylline in two of the six subjects. The results suggest caution in employing a linear model for the individualization of theophylline therapy.