Evaluation of the Effect of Nonlinear Kinetics on Dosage Adjustments of Theophylline

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Abstract
Pharmacokinetics of theophylline at 2 different dosage levels were studied in 6 adult [human] volunteers. Subjects were allowed to reach steady-state serum concentrations of theophylline after 7 days of administration of a substained-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, the mean TBC was 0.76 ml/min per kg; at a dose of 15.7 mg/kg per day, the TBC averaged 0.68 ml/min per kg. For 2 of the subjects, a linear increase in serum concentrations occurred with increasing doses. The remaining 4 subjects showed a saturation of the elimination processes at the higher dosage. The apparent Vmax calculated in these subjects averaged 2923 mg/day. The mean Km was 23.70 .mu.g/ml. Computer-generated serum concentrations produced by a linear increase in doses predicted toxic concentrations of theophylline in 2 of the 6 subjects. Results suggest caution in employing a linear model for the individualization of theophylline therapy.

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