Exercise, induced bronchospasm in asthmatic children as a dose-response model for theophylline

Efficacy and dose-response activity of oral theophylline were evaluated in 21 asthmatic children, using inhibition of exercise-induced bronchospasm (EIB) as a therapeutic marker. An aqueous theophylline suspension free of alcohol, sugar, and dye was found to be effective for prevention of EIB when given in usual maintenance doses of 4 to 6 mg/kg every 6 hours for 3 weeks, following single loading doses of 8 mg/kg. Pulmonary function measurements (FEV1, FEF25%-75%, PEFR) following standardized treadmill exercise stress were signifcantly improved during both acute and chronic theophylline administration compared to pre-drug control evaluations. There were no signs of developing tolerance to theophylline. The drug produced at least 50% inhibition of EIB in 16 to 21 patients treated. Individualized adjustment of maintenance dosage resulted in optimal theophylline serum concentrations of 10 to 18 microgram/ml in 17 patients. Signs of drug toxicity were observed only when serum levels exceeded 20 microgram/ml following loading doses in 6 patients. Although some children required higher maintenance dosage because of variability in theophylline pharmacokinetics, no child experienced adverse effects after dosage adjustment. Serum half-life ranged between 86 and 351 minutes (mean, 259 minutes); mean peak serum concentration of theophylline after 3 weeks of treatment was 14.9 microgram/ml.