Unequal twice-daily, sustained-release theophylline dosing in chronic obstructive pulmonary disease

Three regimens of sustained-release theophylline (SRT), Theostat were administered to 12 male patients with chronic obstructive pulmonary disease in a randomized cross-over trial. Each 7-day treatment consisted of: treatment A--8 mg/kg at 0700 hr and 4 mg/kg at 1900 hr, treatment B--6 mg/kg at 0700 hr and 6 mg/kg at 1900 hr, treatment C--4 mg/kg at 0700 hr and 8 mg/kg at 1900 hr. Peak expiratory flow (PEF) was recorded each day at 0700, 1100, 1500, 1900 and 2300 hr and theophylline plasma levels were determined on the 7th day of each treatment sequence. Cosinor analysis of the data revealed significant circadian rhythms in PEF for each treatment: the mesor (24-hr average) was significantly higher with C and acrophases (phi, peak time of PEF rhythm) were located at 1426 hr for A and 1425 hr for C; a shift of the acrophase to an earlier timing was detected for B (phi = 0958 hr. These findings suggest that an unequal, twice-daily SRT dosing with the greater amount of drug at night may be beneficial in the treatment of COPD.