Circadian variation in theophylline absorption during chronic dosing with a slow release theophylline preparation and the effect of clock time of dosing.

Abstract

1. Eight volunteers were given seven doses of 200 mg of slow release theophylline at either 11.00 h and 23.00 h (regimen 1) or 17.00 h and 05.00 h (regimen 2). At the time of the sixth dose (60 h) hourly blood sampling was started and continued for 24 h. After at least 1 week volunteers crossed over to the other regimen. 2. Volunteers retired to bed at 23.00 h and arose after the 07.00 h sample during both regimens. 3. During regimen 1 there was a marked rise in mean tmax from 3.3 h after dosing at 11.00 h to 9.3 h after dosing at 23.00 h (P less than 0.001). There was also a fall in AUC(0,12) from 89.9 mg l‐1 h after dosing at 11.00 h to 79.0 mg l‐1 h after dosing at 23.00 h. There was no difference in mean Cmax values. 4. During regimen 2 these circadian changes were abolished with mean values after both dosing times lying between those observed during regimen 1. 5. A marked delay in absorption occurs at night and cannot be explained by food intake.

Relative Bioavailability and Bioequivalence Study of Theophylline Sustained Release Formulations

“…Inter-estingly, the theophylline concentrations were somewhat higher after the morning dose of the oral solution when compared to the afternoon and night administration. This observation is in concordance to reports on a circadian behavior of the theophylline pharmacokinetics [10].…”

Respiratory medications and sleep

“…In patients with COPD, a higher serum theophylline concentration improved nocturnal respiratory function without impacting sleep architecture [71]. Of note, circadian variability in theophylline absorption has been described and special attention is required to the timing of doses to ensure adequate nocturnal serum levels [72].…”