PHARMACOKINETIC & SAFETY EVALUATION OF RECOMBINANT HUMAN PROLACTIN

药代动力学

• 批准号: 6265724
• 负责人: Marc Roy Blackman
• 金额: $ 6.52万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6265724
• 关键词: clinical research; clinical trial phase I; drug screening /evaluation; hormone therapy; human subject; pharmacokinetics; prolactin; recombinant proteins; young adult human (21-34)

Prolactin (Prl) is an anterior pituitary peptide hormone which is found in women and men. Prl serum levels in women are substantially higher than in men, and more markedly so during pregnancy. In women, Prl functions in the initiation and maintenance of lactation. Prl is also synthesized at extrapituitary sites where it mediates local function; for example, by lymphocytes where it demonstrates immune system effects much like a cytokine. Prl has potential for therapeutic value in the areas of cancer, human immunodeficiency virus, and as a vaccine adjuvant in the elderly. Currently, there is no information on the effects of administration of rhPrl to humans. This investigation explored the pharmacokinetics, dose proportionality, and relative bioavailability of intravenously and subcutaneoously administered rhPrl in normal young women and men. Subjects were monitored for potential adverse effects of acute short-term rhPrl administration. Finally, preliminary assessments of rhPrl effects on the immune system were conducted. This investigation was a fixed-dose, single blind, dose escalation, Phase I crossover study performed to detect common dose-related adverse effects. We recruited healthy women and men between the ages of twenty-one and thirty-four to participate in the study. Each subject received her/his assigned dose level both intravenously and subcutaneously one week apart and in random order. Twenty-four hours after the study drug administration, routine laboratory tests were performed for safety monitoring and immune function. Subjects were observed for adverse effects during and for twenty- four hours after treatment and discharged after a brief exit history and physical. Each subject was readmitted six days after discharge for a second visit in order to receive their assigned doses of rhPrl by the alternate route. A follow-up history and physical examination along with laboratory testing was performed at no less than 21 days after their second dose. Measurements of serum Prl after treatment were used to derive pharmacokinetic parameters including areas under the concentration time curve from 0 to 12 hours, area under the concentration time curve from zero to infinity, peak Prl concentration (Cmax), time to peak concentration (Tmax), elimination rate (the elimination half-life [t1/2]), volume distribution (Vd), and clearance (Cl). Genzyme Corporation laboratories performed the pK and hrPrl anitbody testing. Immune function testing will consist of delayed hypersensitivity skin tests in vivo and evaluation of immune cell function in vitro performed within the Laboratory of Immunology, Gerontology Research Center(GRC)/NIA. Endocrine studies were performed by the GCRC Core Laboratory and by the Endocrine Section, GRC/NIA laboratory, and routine lab testing for screening and safety data were performed by Quest Diagnostics. All testing of statistical significance will be two-sided, and treatment differences resulting in a p- value <0.05 will be considered significant. Should this study reveal beneficial effects with a low adverse effect profile, we anticipate conducting pK and pD investigations in an aging population, as well as pursuing investigations of the potential immune adjuvant effects of rhPrl.

催乳素(PRL)是一种垂体前叶激素，广泛存在于女性和男性。女性的血清催乳素水平显著高于男性，尤其是在怀孕期间。在女性中，催乳素在哺乳期的启动和维持中起作用。催乳素也是在垂体外部位合成的，在那里它调节局部功能；例如，在淋巴细胞中，它显示出免疫系统的作用很像细胞因子。PRL在癌症、人类免疫缺陷病毒等领域具有潜在的治疗价值，并可作为老年人的疫苗佐剂。目前，还没有关于给药对人类的影响的信息。本研究探讨了正常年轻男女静脉和皮下注射重组人Pr1的药代动力学、剂量比例和相对生物利用度。受试者被监测急性短期给药的潜在不良反应。最后，对重组人Pr1对免疫系统的影响进行了初步评估。这项研究是一项固定剂量、单盲、剂量递增的I期交叉研究，旨在检测常见的剂量相关不良反应。我们招募了年龄在21岁到34岁之间的健康女性和男性参与这项研究。每个受试者每隔一周随机接受静脉内和皮下分配的剂量水平。在研究给药24小时后，进行常规实验室测试以进行安全监测和免疫功能。在治疗期间和治疗后24小时内观察受试者的不良反应，并在短暂的退出病史和体检后出院。每个受试者在出院六天后再次入院进行第二次探视，以便通过替代途径接受分配的剂量的重组人Pr1。在第二次服药后不少于21天进行随访史和体格检查以及实验室检查。药物动力学参数包括血药浓度时间曲线下面积(0~12h)、药时曲线下面积(0~无穷大)、峰浓度(Cmax)、达峰时间(Tmax)、消除速率(消除半衰期[T1/2])、体积分布(Vd)和清除量(CI)。Genzyme公司实验室进行了PK和hrPr1抗体检测。免疫功能测试将包括体内延迟超敏皮肤测试和在NIA老年学研究中心(GRC)免疫学实验室进行的体外免疫细胞功能评估。内分泌研究由GCRC核心实验室和GRC/NIA实验室的内分泌科进行，筛查和安全数据的常规实验室测试由Quest Diagnostics执行。所有有统计学意义的检验将是双侧的，处理差异将被认为是显著的p值&0.05。如果这项研究揭示了副作用较低的有益效果，我们预计将在老龄化人口中进行PK和PD调查，并继续调查rhPr1的潜在免疫佐剂作用。