Data Sciences-Clinical Pharmacology, Grünenthal GmbH, Zieglerstrasse 6, 52078, Aachen, Germany.
Data Sciences-Pharmacometrics, Grünenthal GmbH, Aachen, Germany.
Clin Pharmacokinet. 2018 Jan;57(1):31-50. doi: 10.1007/s40262-017-0545-1.
Cebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple-dose administration.
The basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients. A population PK analysis included two further phase I and six phase II clinical trials.
After oral administration of the immediate-release (IR) formulation, cebranopadol is characterized by a late time to reach maximum plasma concentration [C ] (4-6 h), a long half-value duration [HVD] (14-15 h), and a terminal phase half-life in the range of 62-96 h. After multiple once-daily dosing in patients, an operational half-life (the dosing interval resulting in an accumulation factor [AF] of 2) of 24 h was found to be the relevant factor to describe the multiple-dose PKs of cebranopadol. The time to reach steady state was approximately 2 weeks, the AF was approximately 2, and peak-trough fluctuation (PTF) was low (70-80%). Dose proportionality at steady state was shown for a broad dose range of cebranopadol 200-1600 µg. A two-compartment disposition model with two lagged transition compartments and a first-order elimination process best describes cebranopadol data in healthy subjects and patients after single- and multiple-dose administration.
Cebranopadol formulated as an IR product can be used as a once-daily formulation; it reaches C after only 4-6 h, and has a long HVD and a low PTF. Therefore, from a PK perspective, cebranopadol is an attractive treatment option for patients with chronic pain.
塞来昔布是一种新型的第一类镇痛药，作为孤啡肽/孤啡肽 FQ 肽和阿片肽受体激动剂，具有中枢镇痛活性。它目前正处于治疗慢性疼痛疾病的临床开发阶段。本试验重点研究了口服单剂量和多剂量给药后塞来昔布的临床药代动力学（PK）特性。
通过在健康受试者和患者的六项 I 期临床试验中采用非房室分析方法，评估塞来昔布的基本 PK 特性。群体 PK 分析包括另外两项 I 期和六项 II 期临床试验。
口服速释（IR）制剂后，塞来昔布的特征为达到最大血浆浓度[C ]的时间较晚（4-6 小时），半衰期[HVD]较长（14-15 小时），终末半衰期在 62-96 小时范围内。在患者中多次每日一次给药后，发现操作半衰期（导致累积因子[AF]为 2 的给药间隔）为 24 小时，是描述塞来昔布多次给药 PK 的相关因素。达到稳态的时间约为 2 周，AF 约为 2，峰谷波动（PTF）较低（70-80%）。在塞来昔布 200-1600μg 的广泛剂量范围内，显示出稳态时的剂量比例性。在健康受试者和患者单次和多次给药后，两室分布模型，两个滞后过渡室和一级消除过程最好地描述了塞来昔布的数据。
塞来昔布作为 IR 产品配方可作为每日一次的制剂使用；它在 4-6 小时后即可达到 C ，半衰期长，PTF 低。因此，从 PK 角度来看，塞来昔布是治疗慢性疼痛患者的一种有吸引力的治疗选择。
