缓释型与常规曲马多/对乙酰氨基酚固定剂量复方片剂的药代动力学：一项在健康韩国男性志愿者中开展的开放标签、2 种治疗、多次给药、随机序列交叉研究。

Pharmacokinetics of extended-release versus conventional tramadol/acetaminophen fixed-dose combination tablets: an open-label, 2-treatment, multiple-dose, randomized-sequence crossover study in healthy korean male volunteers.

机构信息

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Republic of Korea.

出版信息

Clin Ther. 2011 Jun;33(6):728-37. doi: 10.1016/j.clinthera.2011.04.023.

DOI:10.1016/j.clinthera.2011.04.023

PMID:21704237

Abstract

BACKGROUND

A fixed-dose combination tablet of tramadol/acetaminophen exhibits both rapid and sustained analgesic effects due to different pharmacologic activities. To prolong analgesia and improve patient convenience, an extended-release (ER) tablet of this agent has been developed.

OBJECTIVE

The aim of this study was to explore the pharmacokinetic profiles of the new ER tramadol/acetaminophen fixed-dose combination and compare them with those of a conventional immediate-release (IR) formulation after multiple dosing as a Phase I clinical exploratory trial.

METHODS

An open-label, randomized, 2-sequence crossover study was conducted in healthy volunteers. All subjects received both formulations for 4 days: either 1 IR tablet (tramadol 37.5 mg/acetaminophen 325 mg) q6h followed by 1 ER tablet (tramadol 75 mg/acetaminophen 650 mg) q12h, or vice versa. A 5-day washout period separated the 2 treatments. Tramadol and acetaminophen concentrations in plasma were determined simultaneously using LC-MS/MS, and the pharmacokinetic properties were analyzed by noncompartmental method. To compare the systemic exposure of the 2 formulations, the geometric mean ratios (GMRs) for AUC(0-12,ss) and the 90% CIs were calculated. Adverse events (AEs) were identified through subject interviews, recording of vital signs, physical examinations, 12-lead electrocardiography, and clinical laboratory assessments.

RESULTS

Twelve healthy, nonsmoking, Korean male subjects completed the study. The mean (SD) age was 24.4 (5.2) years and the mean body weight was 65.1 (6.0) kg. The T(max,ss) for tramadol was delayed until 3 hours after the ER treatment, compared with 1 hour after the IR treatment, whereas the T(max,ss) of acetaminophen was 30 minutes after each treatment. The mean (SD) of AUC(0-12,ss) in the IR and ER formulations was 2789.0 (507.7) and 2638.7 (469.1) µg/h/L for tramadol and 42,635.0 (8711.2) and 40,394.3 (10,127.7) µg/h/L for acetaminophen, respectively. The GMR of ER to IR for AUC(0-12,ss) was 0.95 (90% CI, 0.91-0.99) for tramadol and 0.94 (90% CI, 0.89-0.99) for acetaminophen. A total of 17 AEs occurred in 9 subjects; all AEs were considered mild or moderate and resolved without medical intervention. The most frequent AEs were headache and dizziness (3 cases each).

CONCLUSIONS

The ER formulation displayed a similar AUC(0-12,ss) to that of the IR formulation for tramadol and acetaminophen.

摘要

背景

曲马多/对乙酰氨基酚固定剂量组合片由于具有不同的药理活性，表现出快速和持续的镇痛作用。为了延长镇痛作用并提高患者的便利性，已开发出该药物的一种缓释（ER）片剂。

目的

本研究旨在探索新的 ER 曲马多/对乙酰氨基酚固定剂量组合的药代动力学特征，并在多次给药后作为 I 期临床探索性试验与常规即时释放（IR）制剂进行比较。

方法

一项开放标签、随机、2 序列交叉研究在健康志愿者中进行。所有受试者连续 4 天接受两种制剂：每 6 小时服用 1 片 IR 制剂（曲马多 37.5mg/对乙酰氨基酚 325mg），然后每 12 小时服用 1 片 ER 制剂（曲马多 75mg/对乙酰氨基酚 650mg），或者相反。两种治疗之间有 5 天的洗脱期。采用 LC-MS/MS 同时测定血浆中曲马多和对乙酰氨基酚的浓度，并采用非房室法分析药代动力学特性。为了比较两种制剂的系统暴露，计算 AUC(0-12,ss)的几何均数比值（GMR）和 90%置信区间。通过受试者访谈、生命体征记录、体格检查、12 导联心电图和临床实验室评估来识别不良事件（AE）。

结果

12 名健康、不吸烟的韩国男性完成了这项研究。平均（SD）年龄为 24.4（5.2）岁，平均体重为 65.1（6.0）kg。与 IR 治疗后 1 小时相比，ER 治疗后曲马多的 T(max,ss)延迟至 3 小时，而对乙酰氨基酚的 T(max,ss)则在每次治疗后 30 分钟。IR 和 ER 制剂中 AUC(0-12,ss)的平均值（SD）分别为曲马多 2789.0（507.7）和 2638.7（469.1）µg/h/L，对乙酰氨基酚 42,635.0（8711.2）和 40,394.3（10,127.7）µg/h/L。ER 相对于 IR 的 AUC(0-12,ss)的 GMR 为 0.95（90%CI，0.91-0.99），用于曲马多和 0.94（90%CI，0.89-0.99）用于对乙酰氨基酚。9 名受试者共发生 17 例不良事件；所有不良事件均被认为是轻度或中度，无需医疗干预即可解决。最常见的不良事件是头痛和头晕（各 3 例）。