PHASE I, PILOT, PHARMACOKINETIC STUDY OF AN ORAL TESTOSTERONE PALMITATE FORMU

口服睾酮棕榈酸酯形式的 I 期试验药代动力学研究

• 批准号: 7606191
• 负责人: RONALD Sherwin SWERDLOFF
• 金额: $ 18.97万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7606191
• 关键词: Admission activity; Adult; Adverse effects; Adverse event; Androgen Therapy; Androgens; Biological Availability; Blood; Blood specimen; Breast; Cancer Etiology; Cholesterol; Clinical Chemistry; Collection; Complete Blood Count; Computer Retrieval of Information on Scientific Projects Database; Daily; Data; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Enrollment; Erythrocytes; Funding; Genetic Crossing Over; Grant; Hormones; Hour; Inpatients; Institution; Intestines; Label; Leg; Lipids; Lymphatic; Malignant neoplasm of prostate; Medical History; Metabolism; Methods; Obstruction; Oral; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Preparation; Prostate; Prostate-Specific Antigen; Range; Research; Research Personnel; Resources; Safety; Sampling; Serum; Sex Functioning; Site; Source; Stanolone; Swelling; Symptoms; Tablets; Testing; Time; Treatment Protocols; United States National Institutes of Health; Urinalysis; Urine; Visit; Week; Withdrawal; absorption; base; capsule; day; design; digital; experience; male; men; oral form testosterone; rectal; size; testosterone palmitate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A new oral form of testosterone (T) [Testosterone Palmitate] is designed for potential use in hypogonadal men (men who are deficient in the male hormone). This formulation (preparation) consists of the active ingredient T, in a new lipid based drug delivery system that is designed to favor the absorption of T via the intestinal lymphatics resulting in lower first-pass metabolism and greater bioavailability of orally administered T. The primary objective of this investigator-initiated study is to determine the serum pharmacokinetic (PK) profile and to obtain steady state data for an oral formulation of testosterone palmitate administered once daily and twice daily to hypogonadal men. A secondary objective of the study is to gain information that will provide guidance as to the optimal T dosing regimen for use in an expanded Phase I trial and eventually Phase III pivotal trials. This is an open-label, two-dose, two-period, sequential cross-over, pharmacokinetic study, which will be conducted in six hypogonadal men at one study site. Before subjects are enrolled into the study, they will be screened with a medical history and physical exam (including a digital rectal exam), and lab tests (complete blood counts, clinical chemistry, Prostate Specific Antigen (PSA), hormones, and routine urinalysis). In the first study period, each subject will be asked to take six daily doses of Testosterone Palmitate once a day (two capsules 125 mg) of study medication. In the second period, the subjects will receive the same total daily dose; however, it will be given in a twice daily regimen (one capsule of 125 mg in the morning and evening). For these study periods, subjects will be admitted to the GCRC on the morning of the first dose of study medication and will be confined for one overnight stay at the inpatient unit of the GCRC from approximately 1 hour before dosing and until after collection of the last blood sample. The subjects will take two 125 mg capsules (250 mg total daily dose) of Testosterone Palmitate once a day at 8AM for 6 days. Blood sampling for T and dihydrotestosterone (DHT, a metabolite of T) (8 mL) will be collected at Day 1, 6, 15, and 20, with serial sampling at 30, 15, and 0 minutes pre-dose (0 hours, 8:00 AM), then at 1, 2, 4, 8,12, 16, 20, and 24 hours. Subjects will be required to return to the GCRC for blood draws at 8:00 a.m. the next day (Day 3) and at 8:00 a.m. on Day 5. The subjects will be admitted to the GCRC in-patient unit on the morning of Day 6 from approximately 1 hour before dosing and until after collection of the last blood sample at the 24 hour time point. The subjects will then undergo a wash-out period of one week when they will not be on any androgen treatment. The subjects will return to the inpatient GCRC for the second study period starting on Day 15. They will be confined to an overnight stay at the inpatient unit of the GCRC on Day 15 from 30 minutes before dosing until after collection of the last blood sample. The subjects will take one tablet of 125 mg Testosterone Palmitate twice a day (at 8 AM and 8PM) for 6 days, starting on Day 15. Blood samples for T and DHT will be collected (8mL) beginning 30, 15, and 0 minutes before the morning dose (0 hours, 8:00 AM), then at 1, 2, 4, 8, and 12, hours following both the morning and evening dose administrations. Subjects will be required to return to the GCRC for blood draws at 8:00 a.m. on Day 17 and at 8:00 a.m.on Day 19. The subjects will be admitted to the GCRC in-patient unit on the morning of Day 20 before dosing and until after collection of the last blood sample. The total blood drawn is about 500 mL. Throughout the four in-patient study visits, vital signs will be taken and adverse events and concomitant medications will be recorded. A focused physical exam will be done on each GCRC admission. Safety labs will be done at the last in-patient stay. As the hypogonadal subjects may be withdrawn from T treatment for up to four weeks to participate in this study, during the period of withdrawal the subjects may have symptoms of decreased sexual function and energy. From the previous experience of the investigators and their team, these symptoms are usually mild and do not occur until about three weeks after T treatment withdrawal. Subjects may benefit from the effect of androgen therapy. The anticipated serum T levels achieved after administration would be within the range observed in normal adult men. It is unlikely that the subjects will experience any significant side effects because T is a natural and known male hormone. The study will help to develop a new oral method for androgen replacement in hypogonadal men. Other possible side effects of long-term treatment include increase in red blood cells, breast tenderness, leg swelling, changes in cholesterol levels, increase in prostate size and symptoms of obstruction to urine flow. However, due to the short duration of the T treatment, we do not anticipate that these effects will occur. In addition, there is no clear evidence that show that male hormones cause cancer of the prostate. Patients with cancer of the prostate must not be treated with the male hormone. Men will be screened with a serum PSA level and digital rectal exam.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 一种新型口服形式的睾酮 (T) [棕榈酸睾酮] 旨在用于性腺功能减退男性（缺乏雄性激素的男性）。 该制剂（制剂）由活性成分 T 组成，采用新型脂质药物递送系统，该系统旨在促进 T 通过肠道淋巴管的吸收，从而降低首过代谢并提高口服 T 的生物利用度。 这项研究者发起的研究的主要目的是确定性腺功能减退男性每日一次和每日两次的棕榈酸睾酮口服制剂的血清药代动力学 (PK) 曲线并获得稳态数据。 该研究的第二个目标是获得信息，为扩大的 I 期试验和最终的 III 期关键试验中使用的最佳 T 给药方案提供指导。 这是一项开放标签、两剂、两期、序贯交叉药代动力学研究，将在一个研究中心对六名性腺功能减退男性进行研究。 在受试者参加研究之前，他们将接受病史和体格检查（包括直肠指检）和实验室测试（全血细胞计数、临床化学、前列腺特异性抗原（PSA）、激素和常规尿分析）的筛查。 在第一个研究期间，每位受试者将被要求每天服用六剂棕榈酸睾酮（两粒胶囊，125 毫克）研究药物。 在第二阶段，受试者将接受相同的每日总剂量；然而，它将每天服用两次（早晚各一粒 125 毫克胶囊）。 在这些研究期间，受试者将在第一次服用研究药物的当天早上进入 GCRC，并从给药前约 1 小时到采集最后一个血样后，将被限制在 GCRC 住院部过夜一晚。 受试者将每天上午 8 点服用两粒 125 毫克棕榈酸睾酮胶囊（每日总剂量 250 毫克）一次，持续 6 天。 将在第 1、6、15 和 20 天收集 T 和二氢睾酮 (DHT，T 的代谢物) (8 mL) 的血液采样，并在给药前 30、15 和 0 分钟（0 小时，上午 8:00）、然后在 1、2、4、8、12、16、20 和 24 小时连续采样。 受试者将被要求在第二天（第 3 天）上午 8:00 和第 5 天上午 8:00 返回 GCRC 进行抽血。受试者将在第 6 天早上从给药前约 1 小时到 24 小时时间点收集最后一个血液样本后进入 GCRC 住院部。 然后受试者将经历一周的清除期，在此期间他们将不再接受任何雄激素治疗。 受试者将从第 15 天开始返回 GCRC 住院部进行第二个研究期。第 15 天，从给药前 30 分钟到采集最后一份血样后，他们将被限制在 GCRC 住院部过夜。 从第 15 天开始，受试者每天两次（上午 8 点和晚上 8 点）服用一粒 125 毫克棕榈酸睾酮，持续 6 天。将在早晨给药前 30、15 和 0 分钟（上午 0 点，上午 8:00）开始收集 T 和 DHT 的血液样本（8 mL），然后在早上和晚上给药后的 1、2、4、8 和 12 小时。 受试者将被要求在第 17 天上午 8:00 和第 19 天上午 8:00 返回 GCRC 进行抽血。受试者将在第 20 天早上在给药前被送入 GCRC 住院部，直至采集最后一份血样后。 总抽血量约为500毫升。 在四次住院研究访问中，将采集生命体征并记录不良事件和伴随药物。 每次 GCRC 入院时都会进行重点体检。 安全实验室将在最后一次住院时进行。 由于性腺功能减退受试者可能会退出 T 治疗长达 4 周来参加本研究，因此在退出期间受试者可能会出现性功能和精力下降的症状。 根据研究人员及其团队之前的经验，这些症状通常很轻微，直到 T 治疗停药后约三周才会出现。 受试者可能受益于雄激素治疗的效果。 给药后预期达到的血清 T 水平将在正常成年男性观察到的范围内。 受试者不太可能出现任何明显的副作用，因为 T 是一种天然且已知的雄性激素。 该研究将有助于开发一种新的口服方法来替代性腺功能减退男性的雄激素。 长期治疗的其他可能的副作用包括红细胞增加、乳房压痛、腿部肿胀、胆固醇水平变化、前列腺体积增大和尿流阻塞症状。 然而，由于 T 治疗持续时间短，我们预计不会发生这些影响。 此外，没有明确的证据表明雄性激素会导致前列腺癌。 前列腺癌患者不得接受雄性激素治疗。 男性将通过血清 PSA 水平和直肠指检进行筛查。