Harrison L I, Kehe C R, Ekholm B P, Chang S F, Lavoie K A, Kisicki J C
3M Pharmaceuticals Division, 3M Center, St. Paul, MN 55144.
J Pharm Sci. 1994 Aug;83(8):1171-4. doi: 10.1002/jps.2600830818.
The objective of this study was to determine if the theophylline diurnal variation that has been observed primarily between morning and evening doses of twice-a-day products could be overcome by a once-a-day formulation. Eighteen healthy, nonsmoking, adult male subjects were given 900-mg theophylline doses as three 300-mg once-a-day theophylline capsules 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 statistically equivalent within each treatment, indicating that approximate steady-state conditions were achieved by day 3. Mean serum level profiles over the 24-h interval following the active dose on day 5 were almost superimposable for the morning and evening treatments. All pharmacokinetic parameters were equivalent between the treatments, except for the time to peak serum level (Tmax), which was significantly shorter for the morning dose. Given the flatness of the serum level curves for both treatments, the Tmax difference was judged to be clinically unimportant. A small peak-trough level fluctuation of about 50% was seen with each treatment. We conclude that by designing a dose form in which drug release was the rate-limiting step in drug absorption, the diurnal variation commonly associated with theophylline formulations may be eliminated.
本研究的目的是确定一日一次给药方案是否能够克服主要在一日两次给药产品的早晨和晚上剂量之间观察到的茶碱日变化。18名健康、不吸烟的成年男性受试者以单盲方式，在早晨或晚上服用900毫克茶碱剂量，即三个300毫克的一日一次茶碱胶囊，持续5天。在每次活性药物剂量的中间时段给予匹配的安慰剂胶囊。第3 - 6天的给药前茶碱血清水平在各治疗组内具有统计学等效性，表明到第3天达到了近似稳态条件。第5天活性剂量后24小时内的平均血清水平曲线在早晨和晚上治疗组几乎重叠。除血清水平达峰时间（Tmax）外，各治疗组间所有药代动力学参数均等效，早晨剂量的Tmax明显较短。鉴于两种治疗的血清水平曲线都较为平稳，Tmax差异被判定为临床不重要。每种治疗都观察到约50%的小峰谷水平波动。我们得出结论，通过设计一种药物释放是药物吸收限速步骤的剂型，通常与茶碱制剂相关的日变化可能会消除。
