Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
Clin Pharmacokinet. 2013 Feb;52(2):125-37. doi: 10.1007/s40262-012-0023-8.
Peripherally acting opioids, particularly peripheral κ-opioid agonists, may be effective for treating visceral pain by activating receptors expressed on afferent nerves within the gut.
The objective of this study was to investigate the pharmacokinetic/pharmacodynamic profile of a novel peripherally selective κ-opioid agonist, CR665 (JNJ-38488502), and compare it to that of oxycodone, a non-selective brain-penetrant opioid.
In a randomized, placebo-controlled, double-blind, three-way crossover study, healthy male volunteers were administered CR665 (0.36 mg/kg, intravenous), oxycodone (15 mg, oral) or placebo (intravenous and oral), followed by assessment of visceral pain tolerance thresholds (VPTT) measured as volume of water (mL) in the bag placed on an oesophageal probe. Plasma drug concentration data were used to generate pharmacokinetic models, which were then used to fit the VPTT data using NONMEM(®) VI to generate population pharmacokinetic/pharmacodynamic models.
CR665 kinetics were optimally fitted with a two-compartment model, while oxycodone kinetics were best described by a one-compartment model with transit compartment absorption feeding directly into the central compartment. For both drugs, the plasma concentration effects on VPTT were best fit by a direct linear model, i.e. without the concentration-analgesia delay characteristic of brain-penetrant opioids. The slope of oxycodone (0.089 mL per ng/mL) was steeper than that of CR665 (0.0035 mL per ng/mL) for the plasma drug concentration acting on the VPTT.
The results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.
外周作用阿片类药物，特别是外周 κ 阿片受体激动剂，通过激活肠道内传入神经表达的受体，可能对内脏疼痛有效。
本研究旨在研究一种新型外周选择性 κ 阿片受体激动剂 CR665（JNJ-38488502）的药代动力学/药效学特征，并将其与非选择性脑穿透阿片类药物羟考酮进行比较。
在一项随机、安慰剂对照、三向交叉研究中，健康男性志愿者接受 CR665（0.36mg/kg，静脉注射）、羟考酮（15mg，口服）或安慰剂（静脉注射和口服）治疗，然后评估通过食管探头放置的袋子中的水体积（mL）测量的内脏疼痛耐受阈值（VPTT）。使用 NONMEM（®）VI 生成群体药代动力学/药效学模型，根据药代动力学模型生成药效学模型，以拟合 VPTT 数据。
CR665 动力学最佳拟合为二室模型，而羟考酮动力学最佳拟合为一室模型，其中转运室吸收直接进入中央室。对于两种药物，血浆浓度对 VPTT 的影响最好通过直接线性模型拟合，即没有穿透脑的阿片类药物的浓度-镇痛延迟特征。作用于 VPTT 的血浆药物浓度，羟考酮的斜率（0.089mL/ng/mL）大于 CR665 的斜率（0.0035mL/ng/mL）。
这些结果与 CR665 的外周选择性以及羟考酮的外周作用可能有助于其内脏镇痛疗效一致。
