Summary
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<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<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.
Similar content being viewed by others
References
Weinberger MM, Bronsky EA (1974) Evaluation of oral bronchodilator therapy in asthmatic children. J Pediatr 84: 421–427
Jenne JW, Wyze E, Rood FS, McDonald FM (1972) Pharmacokinetics of theophylline; application to adjustment of the clinical dose of aminophylline. Clin Pharmacol Ther 13: 349–360
Levy G, Koysooko R (1975) Pharmacokinetic analysis of the effect of theophylline on pulmonary function in asthmatic children. J Pediatr 86: 789–793
Mitenko PA, Ogilvie RA (1973) Rational intravenous doses of theophylline. N Engl J Med 289: 600–603
Ellis E, Koysooko R, Levy G (1976) Pharmacokinetics of theophylline in children with asthma. Pediatrics 58: 542–547
Weinberger M, Hendeles L, Bighley L (1978) The relation of product formulation to absorption of oral theophylline. N Engl J Med 299: 852–857
Spangler DL, Kalof DD, Bloom FL, Wittig HJ (1978) Theophylline bioavailability following oral administration of six sustained-release preparations. Ann Allergy 40: 6–11
Foenander T, Birkett DJ, Miners JO, Wing LMH (1980) The simultaneous determination of theophylline, theobromine and caffeine in plasma by high performance liquid chromatography. Clin Biochem 13: 132–134
Weinberger PM (1978) Theophylline for the treatment of asthma. J Pediatr 92: 1–7
Loughnan PM, Sitar DS, Ogilvie RI, Eisen A, Fox Z, Neims AH (1976) Pharmacokinetic analysis of the disposition of intravenous theophylline in young children. J Pediatr 88: 874–879
Jonkman JHG, Berg W, deVries K, de Zeeuw RA, Schoenmaker R, Grimberg N (1981) Disposition and clinical pharmacokinetics of theophylline after administration of a new sustained-release tablet. Eur J Clin Pharmacol 21: 39–44
Russell CJ, Elwood RK, Kinney C, McDevitt DG (1979) Plasma theophylline concentrations following the oral administration of microcrystalline theophylline and a new sustained-release theophylline in normal subjects. Eur J Clin Pharmacol 18: 351–354
Svedmyr N, Mellstrand T, Svedmyr K (1979) Clinical trial of a new slow-release theophylline preparation (‘Neulin’ SR). Curr Med Res Opin (Suppl) 6: 40–44
Jonkman JHG, Berg WC, Koeter GH, Grimberg N, Schoenmaker R, De Zeeuw RA, deVries K (1981) The correlation between “in vitro” dissolution and “in vivo” disposition of sustained-release theophylline tablets. Cong Eur Biopharm Pharmacokinet 1: 182–191
Conard GJ, Jernberg MJ, Wong FW, Mildon CA, French IW (1982) Clinical assessment of theophylline absorption from Theolair-SR and two other sustained-release formulations relative to a conventional formulation. Int J Pharm 10: 259–273
Harrison LI, French IW, Mildon CA (1982) Comparative absorption of theophylline following multiple doses of a sustained-release formulation and an elixir in humans. Clin Ther 4: 489–496
Jones DT, Sears MR (1980) Serum theophylline levels in adult asthmatics: comparison of oral sustained-release and microcrystalline preparations. N Engl Med J 92: 196–198
Lesko LJ, Brousseau D, Canada A, Eastwood G (1980) Temporal variations in trough serum theophylline concentrations at steady-state. J Pharm Sci 69: 358–359
Scott PH, Tabachnik E, MacLeod S, Correia J, Newth C, Levison H (1981) Sustained-release theophylline for childhood asthma: Evidence for circadian variation of theophylline pharmacokinetics. J Pediatr 99: 476–479
Reinberg A, Smolensky MH (1982) Circadian changes of drug disposition in man. Clin Pharmacokinet 7: 401–420
Pedersen S (1982) Treatment of children with a single dose a day of sustained-release theophylline. Br J Clin Pharm 14: 290–291
Thompson PJ, Butcher MA, Frazer LA, Marlin GE (1981) Pharmacokinetics of a single dose of slow release theophylline in patients with chronic lung disease. Br J Clin Pharm 12: 443–444
Jonkman JHG, Schoenmaker R, Grimberg N, de Zeeuw RA (1981) A new in vitro dissolution test for controlled-release theophylline tablets. Int J Pharm 8: 153–156
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Coulthard, K.P., Birkett, D.J., Lines, D.R. et al. Bioavailability and diurnal variation in absorption of sustained release theophylline in asthmatic children. Eur J Clin Pharmacol 25, 667–672 (1983). https://doi.org/10.1007/BF00542356
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00542356