Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
Basic Clin Pharmacol Toxicol. 2020 Mar;126(3):263-276. doi: 10.1111/bcpt.13330. Epub 2019 Oct 28.
Oral controlled-release formulations are playing an ever-increasing role in opioid therapy; however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic-pharmacodynamics of two controlled-release tablet formulations and a liquid formulation of oxycodone in healthy, opioid-naïve volunteers, which can serve as a reference for future patient studies. A semi-double-blinded, three-way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled-release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post-dose. Oxycodone pharmacokinetics was best described by a two-compartment model with first-order absorption. The controlled-release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (k = 0.19 hour ) compared to the oral solution (k = 0.94 hour ). Effects on pupil diameter were delayed relative to plasma (14 minutes half-life) for all formulations and were best described by a proportional E model. The plasma concentration of oxycodone at half-maximum effect was lower in males (31.1 μg/L) compared to females (52.8 μg/L; P < .001). The absorption profile of controlled-release oxycodone formulations provided a prolonged onset and offset of action compared to oral solution oxycodone. The controlled-release formulations showed no differences in pharmacokinetic and pharmacodynamic parameters suggesting that both may be used interchangeably in human beings with normal gastrointestinal function.
口服控释制剂在阿片类药物治疗中发挥着越来越重要的作用；然而，人们对它们对药代动力学和药效学之间关系的影响知之甚少。本研究旨在描述两种控释片剂和一种盐酸羟考酮口服液在健康、阿片类药物初治志愿者中的药代动力学-药效学特征，为未来的患者研究提供参考。进行了一项半双盲、三交叉研究，15 名健康志愿者随机接受两种不同设计的 20mg 单相控释羟考酮片剂和 10mg 口服羟考酮溶液。在给药前和给药后 0.25、0.5、0.75、1、1.5、2、2.33、2.66、3、3.33、3.66、4、5、6、8、12 和 24 小时测定静脉血浆浓度和瞳孔直径。羟考酮药代动力学最好用具有一级吸收的两室模型来描述。与口服溶液（k = 0.94 小时）相比，控释制剂的吸收滞后时间为 0.23 小时，吸收速率常数（k = 0.19 小时）较慢。所有制剂的瞳孔直径作用延迟相对于血浆（半衰期 14 分钟），并且最好由比例 E 模型来描述。与女性（52.8μg/L；P <.001）相比，男性（31.1μg/L）羟考酮的血浆浓度达到半最大效应时较低。与口服溶液羟考酮相比，控释羟考酮制剂的吸收曲线提供了更长的作用开始和结束时间。控释制剂在药代动力学和药效学参数方面没有差异，这表明在具有正常胃肠道功能的人群中，两者可以互换使用。
