Oosterhuis B, Brannan M D, Groen H, Peeters P A, Hempenius J, Radwanski E, Nomeir A A, Affrime M B, Jonkman J H
Pharma Bio-Research International BV, Zuidlaren, The Netherlands.
Ann Allergy Asthma Immunol. 1995 Aug;75(2):157-61.
There is a close relationship between improvement in airway function and the plasma concentration of theophylline, as well as between rapidly rising plasma theophylline concentrations and increased frequency of undesired effects. Development of pharmaceutical formulations and prescribed dosage intervals for theophylline dosage forms should therefore be directed toward providing the most stable plasma concentrations attainable.
To characterize the steady-state biopharmaceutic profile of Uni-Dur following once-daily or twice-daily administration.
Twenty-four adult male volunteers with average theophylline clearance (3.0 and 5.5 L.h-1) received three treatments on separate occasions: Uni-Dur 800 mg once-daily, Uni-Dur 400 mg twice-daily, and Uniphyl 800 mg once-daily. Treatments were taken after a meal for five days with at least 1 week washout between treatment periods. Trough blood samples were collected prior to the AM dose on days 3, 4, and 5, and at specified intervals up to 48 hours after the AM dose on day 5 for subsequent determination of theophylline concentrations in plasma.
The area under the plasma concentration-time curve (AUC; microgram.mL-1.h) for theophylline over 24 hours on day 5 was 187 for Uni-Dur 800 mg once-daily, 187 for Uni-Dur 400 mg twice-daily, and 172 for Uniphyl 800 mg once-daily; the peak plasma concentrations were 10.4, 9.4, and 11.0 micrograms.mL-1 and the trough concentrations were 5.5, 7.2, and 3.5 micrograms.mL-1, respectively; fluctuation index (peak minus trough divided by trough) was 78%, 16%, and 231%, respectively. No further accumulation of theophylline occurred after day 3. No serious nor severe adverse events were reported during any treatment.
Uni-Dur is an extended-release formulation that provides stable plasma concentrations of theophylline over a 24-hour period with less fluctuation than observed with a once-daily reference formulation. In subjects with normal theophylline clearance, Uni-Dur administered twice-daily provided remarkably stable theophylline plasma concentrations over a 24-hour period. Absorption of theophylline from Uni-Dur was not affected by food, and no evidence of dose-dumping was observed. Uni-Dur should provide efficacious theophylline therapy with minimal adverse events in patients with symptoms of asthma and reversible bronchospasm associated with chronic bronchitis and emphysema.
气道功能的改善与茶碱的血浆浓度密切相关，同时血浆茶碱浓度的快速上升与不良反应发生频率的增加也密切相关。因此，茶碱剂型的药物制剂开发和规定的给药间隔应旨在提供可达到的最稳定血浆浓度。
表征每日一次或每日两次给药后优时比（Uni-Dur）的稳态生物药剂学特征。
24名成年男性志愿者，其茶碱平均清除率为（3.0和5.5L·h⁻¹），在不同时间接受三种治疗：每日一次服用800mg优时比，每日两次服用400mg优时比，以及每日一次服用800mg优菲（Uniphyl）。治疗在饭后服用，持续五天，治疗期间之间至少有1周的洗脱期。在第3、4和5天的上午剂量前采集谷血样本，并在第5天上午剂量后长达48小时的特定间隔采集样本，用于随后测定血浆中的茶碱浓度。
第5天，优时比800mg每日一次组24小时内茶碱的血浆浓度-时间曲线下面积（AUC；微克·毫升⁻¹·小时）为187，优时比400mg每日两次组为187，优菲800mg每日一次组为172；血浆峰浓度分别为10.4、9.4和11.0微克·毫升⁻¹，谷浓度分别为5.5、7.2和3.5微克·毫升⁻¹；波动指数（峰浓度减去谷浓度除以谷浓度）分别为78%、16%和231%。第3天后茶碱未进一步蓄积。在任何治疗期间均未报告严重或重度不良事件。
优时比是一种缓释制剂，可在24小时内提供稳定的茶碱血浆浓度，波动小于每日一次的参比制剂。在茶碱清除率正常的受试者中，每日两次服用优时比在24小时内可提供非常稳定的茶碱血浆浓度。优时比中茶碱的吸收不受食物影响，未观察到剂量倾泻的证据。优时比应为患有哮喘症状以及与慢性支气管炎和肺气肿相关的可逆性支气管痉挛的患者提供有效的茶碱治疗，且不良事件最少。
