一种新型镇痛药Cebranopadol的临床药理学特点
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Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic
背景与目的
Cebranopadol是一种具有激动中枢阿片肽受体的类痛啡肽/孤啡肽的FQ肽新型镇痛药物。目前该药物主要应用于临床慢性疼痛的治疗。本研究的主要目的是研究单次或多次口服Cebranopadol后的临床药理学（PK）特性。
方 法
在6名健康志愿者和病人中应用非分隔方法开展临床一期研究用于评估Cebranopadol的一般PK特性。此外，通过Cebranopadol的2例临床一期研究和6例临床二期研究进一步分析该药物的人群PK特性。
结 果
口服Cebranopadol速溶片（IR）后达最大药物血清有效浓度（Cmax）时间长（4-6h），且药物的半衰期（HVD）长（14-15h）以及终末期半衰期波动范围为62-96h。连续多天每日单次给药Cebranopadol后获得的24h动态半衰期（给药间隔周期取决于累计系数（AF）的2倍）可用于研究多剂量Cebranopadol的PKs。Cebranopadol达稳态血药浓度的时间大约为2周,AF值大约为2，波峰潜伏期的波动范围很小（70-80%），稳态相剂量比例的波动范围为200-1600ug。健康志愿者和病人的单次或多次Cebranopadol给药后的PK特性呈两室分布模型且伴有2个较大的过渡隔间以及一级消除形式。
结 论
Cebranopadol速溶片的处方为每日一次服用时，其达Cmax的时间只需4-6h，此外其具有较长的HVD和较低的PTF。因此，根据Cebranopadol的PK特性，其可作为治疗慢性痛疼的很好选择。
原始文献摘要
Kleideiter E, Piana C, Wang S, et al. Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic.[J]. Clinical pharmacokinetics, 2017. DOI:10.1007/s40262-017-0545-1
BACKGROUND AND OBJECTIVES: 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.
METHODS: 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.
RESULTS: After oral administration of the immediate-release (IR) formulation, cebranopadol is characterized by a late time to reach maximum plasma concentration [C max] (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 microg. 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.
CONCLUSIONS: Cebranopadol formulated as an IR product can be used as a once-daily formulation; it reaches C max 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.
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