PHARMACOKINETIC CHAR OF DILAUDID SR RELATIVE TO HYDROMORPHONE

这项三期交叉PK/PD研究的目的如下：第一阶段和第二阶段采用开放标签设计，第三阶段采用双盲随机设计：1)表征三种氢吗啡酮制剂的药代动力学特征——静脉注射（IV）、口服立即释放（IR）和新型口服缓释（SR）。2)测试三种几何增加剂量的新型SR制剂的药代动力学曲线的线性关系。3)表征静脉注射氢吗啡酮在脑电图效应测量中的PK/PD关系。4)表征IR和SR氢吗啡酮的PK/PD关系，以衡量其镇痛效果。5)研究SR氢吗啡酮在主观阿片效应测量中的PK/PD关系。12名正常、健康的受试者（6男6女）参加并完成了研究。6个研究期间隔至少7天，包括静脉注射24小时，ir -氢吗啡酮24小时，sr -氢吗啡酮和安慰剂3个不同剂量的4个周期，每个周期38小时。通过测量一系列动脉和静脉氢吗啡酮浓度来评估药代动力学。进行了药代动力学的室室和非室室分析。静注氢吗啡酮后6小时记录脑电图。分别在口服IR和SR氢吗啡酮后6和30小时建立实验性疼痛模型，量化镇痛效果。通过一个简短的主观阿片类药物效应问卷来评估副作用和对情绪和精神状况的影响。

The objectives of this three phase crossover PK/PD study of an open label design for phase one and two, and a double-blind, randomized design for phase three were as follows: 1) To characterize the pharmacokinetic profile of three hydromorphone formulations - Intravenous (IV), oral immediate release (IR), and new oral slow release (SR). 2) To test for the linearity of the pharmacokinetic profile of three geometrically increasing doses of the novel SR formulation. 3) To characterize the PK/PD relationship of IV hydromorphone for an EEG effect measure. 4) To characterize the PK/PD relationship of IR and SR hydromorphone for an analgesic effect measure. 5) To characterize the PK/PD relationship of SR hydromorphone for a subjective opioid effect measure. Twelve normal, healthy subjects (6 male and 6 female) participated and completed the study. The six study periods were separated by at least 7 days and consisted of a 24-h period for IV administration, a 24-h period for administration of IR-hydromorphone, and 4 periods each lasting 38-h for administration of 3 different doses of SR-hydromorphone and placebo, respectively. The pharmacokinetics were assessed by measuring serial arterial and venous hydromorphone concentrations. Compartment and non-compartmental analysis of the pharmacokinetics was performed. EEG was recorded for 6 hours after IV administration of hydromorphone. Experimental pain models were employed for 6 and 30 hours after oral administration of IR and SR hydromorphone, respectively, to quantify the analgesic efficacy. Side effects and effects on mood and mental condition were assessed with a brief, subjective opioid effects questionnaire.