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Bioavailability and diurnal variation in absorption of sustained release theophylline in asthmatic children
Insights
Sustained release theophylline (Nuelin-SR250) showed diurnal variation in absorption in asthmatic children. Evening doses were absorbed slower, leading to lower predose theophylline concentrations compared to morning doses.
Area of Science:
- Pharmacokinetics
- Pediatric Pharmacology
- Respiratory Medicine
Background:
- Theophylline is a key medication for asthma management.
- Sustained-release formulations aim for consistent drug levels.
- Diurnal variations in drug absorption can impact therapeutic efficacy.
Purpose of the Study:
- To determine the absolute oral bioavailability of Nuelin-SR250 in children with asthma.
- To investigate the diurnal variation in theophylline absorption and its underlying mechanisms.
Main Methods:
- Absolute oral bioavailability of Nuelin-SR250 was assessed in 14 asthmatic children (5-13 years).
- Plasma theophylline concentrations were measured at various time points.
- Diurnal variation in theophylline clearance was evaluated using intravenous aminophylline infusion in 5 children.
Main Results:
- Bioavailability varied significantly between the fourth (38.9%) and sixth (67.9%) doses, indicating delayed steady-state achievement.
- A significant diurnal variation in predose theophylline concentrations was observed, with morning levels 2.9-fold higher than evening levels.
- No diurnal variation in plasma theophylline clearance was found, suggesting absorption differences.
Conclusions:
- The diurnal variation in Nuelin-SR250 predose concentrations is attributed to slower absorption of the evening dose.
- This slower absorption may impact the effectiveness of theophylline therapy in pediatric asthma patients.
- Further investigation into dosing strategies may be warranted to optimize therapeutic outcomes.
Abstract:
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.