Chronopharmacodynamics and kinetics after symmetric and asymmetric multiple theophylline doses in patients with chronic obstructive pulmonary disease.

In a randomized double-blind crossover study, the effects of 4 days of symmetric or asymmetric dosing with sustained-release theophylline (Sabidal-SR) were compared with placebo in ten patients with chronic obstructive pulmonary disease in a stable state. The doses were 450 mg b.i.d. and 270 mg plus 630 mg, respectively. Special attention was paid to circadian rhythms in pharmacokinetics and pharmacodynamic effects, during 24 h of measuring. The peak plasma theophylline concentrations at night with a symmetric dosage were lower than with an asymmetric dosage: 11.5 mg/l (+/- 3.8) and 13.6 mg/l (+/- 4.4), respectively. Both theophylline regimens caused a significant increase in vital capacity (8%) and in forced expiratory volume in one second (15%), and also a decrease of specific viscous work of breathing (49%). There were no significant differences in pharmacodynamic effects between the symmetric and asymmetric dosing regimen. An exception was the heart rate, that increased significantly only with an asymmetric dose. We found no correlation between the theophylline plasma concentration and the changes in lung function and heart rate. Theophylline had no influence on subjective findings of the patients, nor on the oxygen saturation of the blood during sleep.