PHARMACOKINETIC & SAFETY EVALUATION OF RECOMBINANT HUMAN PROLACTIN

催乳素（Prolactin，Prl）是一种存在于女性和男性体内的垂体前叶肽类激素。女性血清Prl水平明显高于男性，在怀孕期间更是如此。在女性中，Prl在哺乳的开始和维持中起作用。Prl也在垂体外的部位合成，在那里它介导局部功能;例如，通过淋巴细胞，在那里它表现出与细胞因子类似的免疫系统作用。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，没有关于影响的信息。 将rhPrl施用于人类。本研究探讨了静脉和皮下注射rhPrl在正常年轻女性中的药代动力学、剂量比例和相对生物利用度， 男人监测受试者急性短期rhPrl给药的潜在不良反应。最后，初步评估了rhPrl对免疫系统的影响。本研究是一项固定剂量、单盲、剂量递增、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。每例受试者以随机顺序接受其指定剂量水平的静脉注射和皮下注射，间隔一周。研究药物给药后24小时，进行常规实验室检查，用于安全性监测和免疫功能。在治疗期间和治疗后24小时观察受试者的不良反应，并在简短的退出史和身体检查后出院。每例受试者在出院后6天再次入院进行第二次访视，以便通过替代途径接受分配剂量的rhPrl。在第二次给药后不少于21天进行随访病史和体格检查沿着以及实验室检查。使用治疗后血清Prl的测量值推导药代动力学参数，包括0 - 1/2小时的浓度-时间曲线下面积、0-无穷大的浓度-时间曲线下面积、Prl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）和清除率（Cl）。 Genzyme Corporation实验室进行了pK和hrPrl抗体检测。免疫功能试验将包括在老年学研究中心（GRC）/NIA免疫学实验室内进行的体内迟发型超敏反应皮肤试验和体外免疫细胞功能评价。内分泌研究由GCRC核心实验室和GRC/NIA实验室内分泌科进行，筛选和安全性数据的常规实验室检测由 由Quest Diagnostics提供。所有统计学显著性检验均为双侧检验，导致p值<0.05的治疗差异将被视为显著。如果本研究显示有益作用且不良作用特征较低，我们预计将在老龄化人群中进行pK和pD研究，并继续研究rhPrl的潜在免疫佐剂作用。

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.