COMPARATIVE PHARMACOKINETICS OF MORNING AND EVENING DOSES OF ONCE-A-DAY THEOPHYLLINE CAPSULES

The objective of this study was to determine if the theophylline diurn al variation that has been observed primarily between morning and even ing doses of twice-a-day products could be overcome by a once-a-day fo rmulation. Eighteen healthy, nonsmoking, adult male subjects were give n 900-mg theophylline doses as three 300-mg once-a-day theophylline ca psules in the morning or evening for 5 days in a single-blind fashion. Matching placebo capsules were administered midway between each dose of active drug. Predose theophylline serum levels on day 3-6 were stat istically equivalent within each treatment, indicating that approximat e steady-state conditions were achieved by day 3. Mean serum level pro files over the 24-h interval following the active dose on day 5 were a lmost superimposable for the morning and evening treatments. All pharm acokinetic parameters were equivalent between the treatments, except f or the time to peak serum level (T-max), which was significantly short er for the morning dose. Given the flatness of the serum level curves for both treatments, the T-max difference was judged to be clinically unimportant. A small peak-trough level fluctuation of about 50% was se en with each treatment. We conclude that by designing a dose form in w hich drug release was the rate-limiting step in drug absorption, the d iurnal variation commonly associated with theophylline formulations ma y be eliminated.