Single- and Multiple-Dose Pharmacokinetic Evaluation of Oxycodone and Naloxone in an Opioid Agonist/Antagonist Prolonged-Release Combination in Healthy Adult Volunteers
Single- and Multiple-Dose Pharmacokinetic Evaluation of Oxycodone and Naloxone in an Opioid Agonist/Antagonist Prolonged-Release Combination in Healthy Adult Volunteers
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DOI：
10.1016/j.clinthera.2008.11.008
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发表时间：
2008-11-01
影响因子：
3.2
通讯作者：
Reimer, Karen
中科院分区：
文献类型：
--
作者：
Smith, Kevin;Hopp, Michael;Reimer, Karen
背景：越来越多的证据支持对慢性疼痛患者长期使用阿片类药物相关不良事件（ae）进行预防性管理的必要性。肠道功能障碍的症状，如便秘，可能对患者的生活质量和继续阿片类药物治疗的意愿产生重大影响，因此应积极管理，以确保患者能够继续有效的疼痛管理。固定剂量延长释放氧可酮/纳洛酮（OXN）可能是一种有效的镇痛治疗方法，可降低阿片类药物引起便秘的风险。目的：本文的目的是报道氧可酮PR和纳洛酮PR在健康受试者中单剂量和多剂量生物等效性研究的药代动力学结果。方法：两项研究均为开放标签、随机交叉研究，在健康成年男性和女性受试者中进行。在单剂量研究中，受试者被随机分配到4个治疗组中的1个：OXN FDC （4 × 10/ 5mg, 2 × 20/ 10mg，或1 × 40/ 20mg剂量强度[每次总联合剂量为40/ 20mg]）或羟考酮PR 40 mg +纳洛酮PR 20 mg，以单独的配方给药。在多剂量研究中，34名受试者被随机分配到3个治疗组中的一个：OXN FDC 40/ 20mg，羟考酮PR 40 mg，或纳洛酮PR 20 mg。如果用于相对生物利用度计算的90% ci在预定的80%至125%范围内，则认为处理具有生物等效性。研究者在每次研究访问时对ae进行评估。结果：单剂量研究纳入28例受试者（男性22例，女性6例），平均[SD]年龄32.3[5.4]岁，体重75.5 [9.3]kg，体重指数[BMI] 24.2 [2.5] kg/m(2))。氧可酮与氧可酮PR +纳洛酮PR的平均血浆氧可酮浓度-时间曲线相似。羟考酮的平均（SD） AUC(t)值分别为：OXN 10/5、20/10和40/20 mg，羟考酮PR +纳洛酮PR分别为473.49（72.16）、491.22（82.18）、488.89（91.04）和502.28 (84.1.3)ng。分别为h /毫升;平均C-max值分别为34.91（4.36）、35.73（4.93）、34.46（5.03）和40.45 (4.71)ng/mL。纳洛酮-3-葡萄糖醛酸盐（纳洛酮的主要分析物）在OXN为1015、20/10和40/20 mg时的平均（SD） AUC(t)值分别为539.93（142.24）、522.45（128.57）、520.10（133.18）和523.37 (11.9.75)ng。分别为h /毫升;平均C-max值分别为62.01（15.96）、63.62（19.51）、61.95（18.37）和63.55 (16.75)ng/mL。处理之间没有统计学上的显著差异，每个处理比较的结果是90%的ci在生物等效性范围内。多剂量稳态生物等效性研究包括34名受试者（男性28名，女性6名），平均[SD]年龄36[9.4]岁，体重78.9 [11.7]kg, BMI 24.6 [1.9] kg/m(2))。除纳洛酮-3-葡糖苷C-min、C-ss值外，两组间无显著差异。OXN联合用药和纳洛酮PR片的平均C-min、C-ss值分别为22.6和24.0 ng/mL。在多剂量研究中，OXN、羟考酮PR和纳洛酮PR最常报道的不良反应是头痛（分别为7%、26%和17%）、厌食（10%、16%和13%）和恶心（10%、13%和7%）。结论：单剂量研究的结果符合fdc和单一组分在给药剂量范围内生物等效性的监管定义。根据监管定义，OXN FDC的药代动力学性质与氧可酮PR +纳洛酮PR作为单独制剂的药代动力学性质相似。这些发现与多剂量稳态生物等效性研究的结果一致。在这群健康志愿者中，羟考酮的药代动力学特性显然没有受到羟考酮联合用药的显著影响，从羟考酮中提取纳洛酮-3-葡萄糖醛酸盐的可得性与从纳洛酮PR片中提取的可得性相似。这些发现表明，在FDC中同时使用羟考酮PR和纳洛酮PR不会显著影响其任何成分在这些受试者中的生物利用度。（中国医学杂志，2008;30:2051-2068）
Background: There is an increasing body of evidence supporting the need for prophylactic management of the adverse events (AEs) associated with long-term opioid use in patients with chronic pain. Symptoms of bowel dysfunction, such as constipation, may have a significant impact on a patient's quality of life and willingness to continue opioid therapy, and therefore should be managed proactively to ensure that the patient can continue effective pain management. The fixed-dose combination (FDC) prolonged-release (PR) oxycodone/naloxone (OXN) may be an effective therapeutic approach to delivering analgesia, with a reduced risk for opioid-induced constipation.Objective: The aim of this paper was to report the pharmacokinetic results from a single-dose study and a multiple-dose bioequivalence study of OXN versus separate formulations of oxycodone PR and naloxone PR administered concurrently in healthy subjects.Methods: Both studies were open-label, randomized crossover studies in healthy adult male and female subjects. In the single-dose study, subjects were randomly assigned to 1 of 4 treatment groups: OXN FDC (4 x 10/5-mg, 2 x 20/10-mg, or 1 x 40/20-mg dose strength [each given at a total combined dose of 40/20 mg]) or oxycodone PR 40 mg + naloxone PR 20 mg given in separate formulations. In the multiple-dose study, 34 subjects were randomly assigned to 1 of 3 treatment groups: OXN FDC 40/20 mg, oxycodone PR 40 mg, or naloxone PR 20 mg. Treatments were considered bioequivalent if the 90% CIs for relative bioavailability calculations fell within a predetermined range of 80% to 125%. AEs were assessed by the investigator at each study visit.Results: The single-dose study included 28 subjects (22 men, 6 women; mean [SD] age, 32.3 [5.4] years; weight, 75.5 [9.3] kg; and body mass index [BMI], 24.2 [2.5] kg/m(2)). The mean plasma oxycodone concentration-time curves for OXN and oxycodone PR + naloxone PR were similar. With oxycodone, the mean (SD) AUC(t) values with OXN 10/5, 20/10, and 40/20 mg and oxycodone PR + naloxone PR were 473.49 (72.16), 491.22 (82.18), 488.89 (91.04), and 502.28 (84.1.3) ng . h/mL, respectively; mean C-max values were 34.91 (4.36), 35.73 (4.93), 34.46 (5.03), and 40.45 (4.71) ng/mL. For naloxone-3-glucuronide (the primary analyte of naloxone), the mean (SD) AUC(t) values with OXN 1015, 20/10, and 40/20 mg and oxycodone PR + naloxone PR were 539.93 (142.24), 522.45 (128.57), 520.10 (133.18), and 523.37 (11.9.75) ng . h/mL, respectively; mean C-max values were 62.01 (15.96), 63.62 (19.51), 61.95 (18.37), and 63.55 (16.75) ng/mL. There were no statistically significant differences between the treatments, and each of the treatment comparisons resulted in 90% CIs within the range for bioequivalence. The multiple-dose steady-state bioequivalence study included 34 subjects (28 men, 6 women; mean [SD] age, 36 [9.4] years; weight, 78.9 [11.7] kg; and BMI, 24.6 [1.9] kg/m(2)). No significant differences were observed between the treatments, with the exception of naloxone-3-glucuronide C-min,C-ss values. Mean C-min,C-ss values of 22.6 and 24.0 ng/mL were obtained for the OXN combination and naloxone PR tablet, respectively. In the multiple-dose study, the most frequently reported AEs with OXN, oxycodone PR, and naloxone PR were headache (7%, 26%, and 17%, respectively), anorexia (10%, 16%, and 13%), and nausea (10%, 13%, and 7%).Conclusions: The results from the single-dose study were Consistent with the regulatory definition of bio-equivalence of the FDCs and single components across the range of doses administered. The pharmacokinetic properties of the OXN FDC were similar to those of oxycodone PR + naloxone PR given as separate formulations, based on the regulatory definition. These findings were consistent with the results of the multiple-dose steady-state bioequivalence study. In this population of healthy Volunteers, the pharmacokinetic properties of oxycodone apparently were not significantly influenced by administering oxycodone in a combination product, and the availability of naloxone-3-glucuronide from OXN was similar to that from the naloxone PR tablet. These findings suggest that the coadministration of oxycodone PR and naloxone PR in an FDC would not significantly affect the bioavailability of either of its constituents in these subjects. (Clin Ther. 2008;30:2051-2068) (C) 2008 Excerpta Medica Inc.