Bioavailability and diurnal variation in absorption of sustained release theophylline in asthmatic children.

The absolute oral bioavailability of a sustained release theophylline tablet (Nuelin-SR250), given 12 hourly was determined in 14 asthmatic children aged 5 to 13 years. In 4 of the patients, mean bioavailability of the fourth dose was 38.9 +/- 8.4% and that of the sixth dose was 67.9 +/- 25.9% (p less than 0.05) in the other ten patients. This suggests steady-state had not been achieved after four doses. In the initial study with 9 patients, a significant diurnal variation in predose plasma theophylline concentrations was observed, as the mean morning predose concentrations were 2.9 fold greater than the mean evening predose concentrations (p less than 0.005). Dual peak plasma concentrations occurred in 5 out of the 9 patients. The mechanism of this diurnal variation was investigated in a further 5 asthmatic children (10.8 years +/- 1.6). Morning and night steady-state plasma theophylline concentrations during a continuous intravenous infusion of aminophylline were not different (14.9 +/- 5.3 mg/l vs. 15.6 +/- 5.9 mg/l), demonstrating that there was no diurnal variation in the plasma clearance of theophylline. The diurnal variation in predose concentrations with Neulin-SR250 was confirmed with the morning concentrations again being 2.6 fold greater than those in the evening. However, bioavailability was not significantly different for day (09.00-21.00) and night (21.00-09.00) dosing intervals after doses 6 and 7 respectively of Nuelin-SR250. The plasma concentration versus time profiles suggested that the diurnal variation in predose concentrations was due to slower absorption of the evening dose.