Scheidel Bernhard, Maritz Martina A, Gschwind Yves J, Steigerwald Kerstin, Guth Volker, Kovacs Peter, Rey Helene
Int J Clin Pharmacol Ther. 2017 Nov;55(11):881-890. doi: 10.5414/CP203005.
To evaluate and to compare the bioavailability, the influence of food intake on the bioavailability, and the safety and tolerability of a newly-developed oxycodone once-daily (OOD) prolonged-release tablet with an established oxycodone twice-daily (OTD) prolonged-release tablet after single-dose administration under fasting or fed conditions as well as after multiple-dose administration.
Three single-center, open-label, randomized, balanced, two-treatment, two-period, two-sequence crossover studies were conducted. In each study, 36 healthy volunteers were randomized to receive 10 mg oxycodone daily as OOD (oxycodone HCL 10-mg PR tablets XL (Develco Pharma Schweiz AG, Pratteln, Switzerland); administration of 1 tablet in the morning) or as OTD (reference formulation: oxygesic 5-mg tablets (Mundipharma GmbH, Limburg an der Lahn, Germany); administration of 1 tablet in the morning and 1 tablet in the evening). Tablets were administered once daily or twice daily under fasting conditions (study 1) or under fed conditions (study 2) as well as after multiple-dose administration (study 3). A sufficient number of blood samples were taken for describing plasma profiles and for calculation of pharmacokinetic parameters. Plasma concentrations of oxycodone were determined by LC-MS/MS. Safety and tolerability were monitored and assessed in all three studies.
Plasma profiles of OOD reveal sustained concentrations of oxycodone over the complete dosing interval of 24 hours. In comparison to the OTD reference formulation, the OOD test formulation showed a slightly slower increase of concentrations within the absorption phase and similar plasma concentrations at the maximum and at the end of the dosing interval (24 hours). Extent of bioavailability (AUC), maximum plasma concentrations (C), and plasma concentrations at the end of the dosing interval (C) of OOD could be classified as comparable to OTD considering 90% confidence intervals (CIs) and acceptance limits of 80.00 - 125.00%. Bioavailability of OOD was not influenced by concomitant food intake. OOD and OTD were generally well tolerated, a difference between the two products could not be observed.
CONCLUSION: The new 10-mg OOD formulation provides sustained oxycodone plasma concentrations over the dosing interval of 24 hours and is suitable for once-daily administration. Bioavailability of OOD could be classified as comparable to the twice-daily administration of the OTD reference formulation. The new formulation widens and optimizes the range of strong opioid drug products in patient-centered therapy of chronic pain with simplified dosing and better compliance. .
评估并比较一种新研发的每日一次（OOD）缓释羟考酮片与已上市的每日两次（OTD）缓释羟考酮片单剂量给药后在禁食或进食条件下以及多剂量给药后的生物利用度、食物摄入对生物利用度的影响、安全性和耐受性。
进行了三项单中心、开放标签、随机、均衡、双治疗、双周期、双序列交叉研究。在每项研究中，36名健康志愿者被随机分为接受每日10mg羟考酮的OOD给药方案（盐酸羟考酮10mg PR片XL（瑞士普拉特尔恩的Develco Pharma Schweiz AG公司）；早晨服用1片）或OTD给药方案（参比制剂：奥施康定5mg片（德国林堡 an der Lahn的Mundipharma GmbH公司）；早晨服用1片，晚上服用1片）。在禁食条件下（研究1）、进食条件下（研究2）以及多剂量给药后（研究3），片剂每日给药一次或两次。采集足够数量的血样以描绘血浆浓度曲线并计算药代动力学参数。通过液相色谱 - 串联质谱法测定血浆中羟考酮的浓度。在所有三项研究中监测并评估安全性和耐受性。
OOD的血浆浓度曲线显示在24小时的整个给药间隔内羟考酮浓度持续存在。与OTD参比制剂相比，OOD受试制剂在吸收相内浓度升高稍慢，在给药间隔（24小时）的最大值和结束时血浆浓度相似。考虑90%置信区间（CIs）和80.00 - 125.00%的接受限度，OOD的生物利用度（AUC）、最大血浆浓度（C）以及给药间隔结束时的血浆浓度（C）可归类为与OTD相当。OOD的生物利用度不受食物摄入的影响。OOD和OTD总体耐受性良好，未观察到两种产品之间存在差异。
新的10mg OOD制剂在24小时给药间隔内提供持续的羟考酮血浆浓度，适合每日一次给药。OOD的生物利用度可归类为与OTD参比制剂每日两次给药相当。新制剂拓宽并优化了强阿片类药物产品的范围，用于以患者为中心的慢性疼痛治疗，具有简化给药和更好的依从性。
