Dose-dependent kinetics for theophylline: observations among ambulatory asthmatic children

In order to assess the clinical impact of dose-dependent kinetics for theophylline, the relationship between serum concentration and daily dosage among patients under the care of the University of Iowa Pediatric Allergy and Pulmonary Service was examined. Dosage was titrated clinically, with the final adjustment based on a serum theophylline measurement. Of 200 charts initially reviewed, 42 patients were found in whom at least two peak serum concentrations had been measured at different doses of the same theophylline preparation. In 30 (15% of initial 200) of these 42 patients, the percent change in serum concentration exceeded the percent change in dose by at least 50%. Subsequently, 300 additional charts were reviewed to identify a total of 26 patients with three steady-state serum concentrations at three different doses. Only five of these patients demonstrated a linear relationship between dose and serum concentration; the other 21 demonstrated disproportionate changes compatible with parallel first-order and dose-dependent kinetics. Thus, clinically important dose-dependent kinetics for theophylline occur in at least 15% of children, and theophylline dosage therefore must be adjusted in small increments in order to avoid disproportionately large changes in serum concentration with consequent risks of toxicity during continuous therapy.