Clinical Pharmacology Sciences Modeling and Simulation, Medicines Development Center, Eisai Inc., Woodcliff Lake, New Jersey, USA.
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA.
J Clin Pharmacol. 2022 Sep;62(9):1177-1190. doi: 10.1002/jcph.2058. Epub 2022 May 6.
Little is known about how opioid responses vary by age and in the presence of alcohol consumption. This model-based pharmacokinetic (PK)-pharmacodynamic (PD) analysis quantified the impact of age and alcohol use on pupillometry and cold pressor test (CPT) PD based on data from an open-label study of a single, immediate-release 10-mg oral oxycodone in middle-age and older adults (aged 35-85) without severe functional limitations. PK and pupillometry assessments were obtained on 11 occasions over 8 hours. Cold pressor test was administered at 1.5, 5, and 8 hours after oxycodone dosing. The study population consisted of 62 older adults (aged ≥60) and 66 middle-aged adults (aged 35-59), with 82% meeting the unhealthy drinking criteria. Oral oxycodone PK were well described using a 1-compartment model with a sequential 0 to first-order absorption process. Inhibitory maximum effect and linear direct effect PD models described the respective pupillometry and cold pressor test data using simultaneous PK-PD analysis in MONOLIX. Recent alcohol use measures were selected a priori as covariates. This analysis demonstrated an influence of age on clearance and body weight on the distribution volume of oxycodone; alcohol consumption was not noted to alter oxycodone PK. Oxycodone pupillometry PD were influenced by the level of subject-reported alcohol consumption (Alcohol Use Disorders Identification Test for Consumption), alcohol use biomarker-blood phosphatidylethanol, previous cannabis use, and age. Over the opioid exposure range of the study, none of the covariables including alcohol and age were noted to affect cold pressor test pharmacodynamics. Additional clinical studies are needed to further investigate the clinical consequences of opioid-alcohol-age interaction.
关于阿片类药物反应如何随年龄和酒精摄入而变化，目前知之甚少。本基于模型的药代动力学（PK）-药效动力学（PD）分析根据一项单次、速释 10 毫克口服羟考酮在中年和老年（年龄 35-85 岁）无严重功能限制的成年人中进行的开放标签研究数据，量化了年龄和酒精使用对瞳孔测量和冷加压试验（CPT）PD 的影响。在 8 小时内进行了 11 次 PK 和瞳孔测量评估。在羟考酮给药后 1.5、5 和 8 小时进行冷加压试验。研究人群包括 62 名老年（年龄≥60 岁）和 66 名中年成年人（年龄 35-59 岁），其中 82%符合不健康饮酒标准。口服羟考酮 PK 采用具有序贯 0 至一阶吸收过程的 1 室模型进行了很好的描述。使用 MONOLIX 中的同时 PK-PD 分析，抑制最大效应和线性直接效应 PD 模型分别描述了相应的瞳孔测量和冷加压试验数据。最近的酒精使用测量值被预先选为协变量。该分析表明年龄对清除率有影响，体重对羟考酮分布容积有影响；未观察到酒精消耗改变羟考酮 PK。羟考酮瞳孔测量 PD 受到受试者报告的酒精摄入量（用于消费的酒精使用障碍识别测试）、酒精使用生物标志物-血磷乙醇、以前的大麻使用和年龄的影响。在研究的阿片类药物暴露范围内，包括酒精和年龄在内的所有协变量均未被认为会影响冷加压试验药效学。需要进一步的临床研究来进一步探讨阿片类药物-酒精-年龄相互作用的临床后果。
