Tompson Debra J, Vearer Deborah
Clinical Pharmacokinetics, Modelling and Simulation, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK.
Clin Ther. 2007 Dec;29(12):2654-66. doi: 10.1016/j.clinthera.2007.12.010.
Ropinirole 24-hour prolonged release is a new once-daily formulation of ropinirole that provides continuous delivery of ropinirole over 24 hours.
The studies described here were conducted to characterize the steady-state pharmacokinetics of ropinirole 24-hour prolonged release in patients with Parkinson's disease.
Study 164 was a 2-part study; Part A employed a crossover design to assess the relative bioavailability of steady-state ropinirole 24-hour prolonged release 8 mg QD and ropinirole immediate release 2.5 mg TID, and Part B evaluated the effect of food intake on the rate and extent of ropinirole absorption from ropinirole 24-hour prolonged release 8 mg QD. Study 165 assessed the dose proportionality of ropinirole 24-hour prolonged release 2-, 4-, and 8-mg tablets and the dose-strength equivalence of four 2-mg tablets compared with one 8-mg tablet. Intensive pharmacokinetic blood sampling was performed over 24 hours. Steady-state C(max), C(min), AUC from time zero to 24 hours after dosing (AUC(0-24)), and T(max) were determined by noncompartmental methods.
Twenty-three patients (91% white; mean age, 67 years [range, 34-80 years] mean weight, 84.5 kg [range, 57-103 kg]) were randomized to treatment in Study 164. Twenty-eight patients (86% white; mean age, 67 years [range, 47-87 years] mean weight, 84.6 kg [range, 49-128 kg]) were randomized to treatment in Study 165. Compared with ropinirole immediate release, ropinirole 24-hour prolonged release had a smooth plasma concentration-time profile over 24 hours. AUC(0-24) and C(min) values, normalized to a 1-mg dose, were similar for ropinirole 24-hour prolonged release and ropinirole immediate release. Dose-normalized C(max) was slightly lower (approximately 12%) for ropinirole 24-hour prolonged release than for ropinirole immediate release. The AUC(0-24) and C(min) were similar in the fed and fasted states. The pharmacokinetics of ropinirole 24-hour prolonged release were dose proportional, as indicated by the estimated slopes for AUC(0-24) and C(max) being close to unity, along with the 90% CIs being contained within the predefined dose-range-adjusted limits. For C(min), the slope was close to unity (1.04), but the upper end of the 90% CI fell marginally outside the predefined range. Statistical analysis indicated that the dose strengths were equivalent when a single pharmacokinetic outlier was excluded from the analysis.
Ropinirole 24-hour prolonged release provided continuous delivery of ropinirole over 24 hours, resulting in a smooth plasma concentration-time profile, and food had no significant effect on absorption. Dose-normalized AUC(0-24) and C(min) were similar for both formulations, and dose-normalized C(max) was slightly lower for ropinirole 24-hour prolonged release. These relative bioavailability data indicated that patients may switch overnight from ropinirole immediate release to ropinirole 24-hour prolonged release while maintaining similar daily exposure. The pharmacokinetics of ropinirole were dose proportional over the range from 2 to 8 mg. The dose strengths of four 2-mg tablets and one 8-mg tablet of ropinirole 24-hour prolonged release were found to be equivalent.
罗匹尼罗24小时长效制剂是一种新型的罗匹尼罗每日一次给药制剂，可在24小时内持续释放罗匹尼罗。
进行此处描述的研究以表征帕金森病患者中罗匹尼罗24小时长效制剂的稳态药代动力学。
研究164为一项分为两部分的研究；A部分采用交叉设计评估罗匹尼罗24小时长效制剂8mg每日一次和罗匹尼罗速释制剂2.5mg每日三次的稳态相对生物利用度，B部分评估进食对罗匹尼罗24小时长效制剂8mg每日一次的罗匹尼罗吸收速率和程度的影响。研究165评估罗匹尼罗24小时长效制剂2mg、4mg和8mg片剂的剂量比例性以及四片2mg片剂与一片8mg片剂的剂量强度等效性。在24小时内进行密集的药代动力学血样采集。通过非房室方法测定稳态C(max)、C(min)、给药后0至24小时的AUC（AUC(0 - 24)）以及T(max)。
23名患者（91%为白人；平均年龄67岁[范围34 - 80岁]，平均体重84.5kg[范围57 - 103kg]）被随机分配至研究164进行治疗。28名患者（86%为白人；平均年龄67岁[范围47 - 87岁]，平均体重84.6kg[范围49 - 128kg]）被随机分配至研究165进行治疗。与罗匹尼罗速释制剂相比，罗匹尼罗24小时长效制剂在24小时内具有平稳的血浆浓度 - 时间曲线。以1mg剂量进行标准化后，罗匹尼罗24小时长效制剂和罗匹尼罗速释制剂的AUC(0 - 24)和C(min)值相似。罗匹尼罗24小时长效制剂的剂量标准化C(max)比罗匹尼罗速释制剂略低（约12%）。进食和禁食状态下的AUC(0 - 24)和C(min)相似。罗匹尼罗24小时长效制剂的药代动力学呈剂量比例性，这由AUC(0 - 24)和C(max)的估计斜率接近1以及90%置信区间包含在预先定义的剂量范围调整限度内表明。对于C(min)，斜率接近1（1.04），但90%置信区间的上限略超出预先定义的范围。统计分析表明，当从分析中排除一个药代动力学异常值时，剂量强度是等效的。
罗匹尼罗24小时长效制剂在24小时内持续释放罗匹尼罗，导致血浆浓度 - 时间曲线平稳，且食物对吸收无显著影响。两种制剂的剂量标准化AUC(0 - 24)和C(min)相似，罗匹尼罗24小时长效制剂的剂量标准化C(max)略低。这些相对生物利用度数据表明，患者可以在夜间从罗匹尼罗速释制剂转换为罗匹尼罗2小时长效制剂，同时保持相似的每日暴露量。罗匹尼罗在2至8mg范围内的药代动力学呈剂量比例性。发现罗匹尼罗24小时长效制剂的四片2mg片剂和一片8mg片剂剂量强度等效。
