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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 一种新的口服形式的睾酮（T）[棕榈酸睾酮]旨在用于性腺功能减退的男性（男性激素缺乏的男性）的潜在用途。 该制剂（制剂）由活性成分T组成，在一种新的基于脂质的药物递送系统中，该系统被设计为有利于T通过肠道代谢的吸收，从而导致口服给药的T的较低的首过代谢和较高的生物利用度。 本研究的主要目的是确定血清药代动力学（PK）曲线，并获得稳态数据的口服制剂的睾酮棕榈酸酯每日一次和每日两次给药的性腺功能减退的男性。 本研究的次要目的是获得将为扩展I期试验和最终III期关键试验中使用的最佳T给药方案提供指导的信息。 这是一项开放标签、两次给药、两阶段、序贯交叉、药代动力学研究，将在一个研究中心的6名性腺功能减退男性中进行。 在受试者入组研究之前，将通过病史和体格检查（包括直肠指检）以及实验室检查（全血细胞计数、临床生化、前列腺特异性抗原（PSA）、激素和常规尿分析）对受试者进行筛选。 在第一个研究阶段，将要求每例受试者每天服用一次（2粒胶囊125 mg）棕榈酸替尼酯，每日6次。 在第二阶段，受试者将接受相同的每日总剂量;但是，将以每日两次方案给药（早晚各服用一粒125 mg胶囊）。 对于这些研究阶段，受试者将在研究药物首次给药当天早晨入住GCRC，并从给药前约1小时至采集末次血样后在GCRC住院部过夜。 受试者将在每天上午8点服用2粒125 mg棕榈酸替尼酯胶囊（每日总剂量为250 mg），持续6天。 将在第1、6、15和20天采集T和双氢睾酮（DHT，T的代谢产物）（8 mL）的血样，在给药前30、15和0分钟（0小时，8：00 AM），然后在1、2、4、8、12、16、20和24小时连续采样。 要求受试者在第二天（第3天）上午8：00和第5天上午8：00返回GCRC进行采血。 受试者将在第6天早晨从给药前约1小时至24小时时间点采集最后一份血样后入住GCRC住院部。 然后受试者将经历一周的洗脱期，期间他们将不接受任何雄激素治疗。 从第15天开始，受试者将返回住院GCRC接受第二个研究阶段。 第15天，从给药前30分钟至采集末次血样后，受试者将在GCRC的住院部过夜。 从第15天开始，受试者将服用一片125 mg棕榈酸替尼替尼，每日两次（上午8点和下午8点），持续6天。 将在早晨给药前30、15和0分钟（0小时，8：00 AM），然后在早晨和晚上给药后1、2、4、8和12小时采集T和DHT血样（8 mL）。 要求受试者在第17天上午8：00和第19天上午8：00返回GCRC进行采血。 受试者将在给药前第20天早晨入住GCRC住院部，直至采集末次血样后。 抽取的血液总量约为500 mL。 在4次住院研究访视期间，将采集生命体征，并记录不良事件和合并用药。 一个集中的体检将在每个GCRC入场完成。 安全性实验室检查将在患者最后一次住院时进行。 由于性腺功能减退的受试者可能会退出T治疗长达4周以参与本研究，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。 从研究者和他们的团队以前的经验来看，这些症状通常是轻微的，直到T治疗停药后大约三周才出现。 受试者可能受益于雄激素治疗的效果。 给药后达到的预期血清T水平将在正常成年男性中观察到的范围内。 受试者不太可能经历任何显著的副作用，因为T是一种天然且已知的男性激素。 该研究将有助于开发一种新的口服雄激素替代治疗性腺功能减退男性的方法。 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，前列腺大小增加和尿流阻塞症状。 然而，由于T治疗的持续时间短，我们预计不会发生这些影响。 此外，没有明确的证据表明男性激素会导致前列腺癌。 前列腺癌患者不能用雄性激素治疗。 男性将通过血清PSA水平和直肠指检进行筛查。