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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 一种新的口服睾丸激素（T）[睾丸激素棕榈酸酯]设计用于性低肿瘤男性（雄性激素不足的男性）的潜在用途。 这种配方（制剂）由活性成分T组成，在新的基于脂质的药物输送系统中，该系统旨在通过肠道淋巴管吸收T，从而导致较低的第一频繁代谢和口服TT的生物利用度更高。 这项研究者发起的研究的主要目的是确定血清药代动力学（PK）谱，并获得稳态数据，以每天给予一次睾丸激素棕榈酸酯的口服配方，每天两次对性降低男性。 该研究的次要目的是获取信息，以提供有关在扩展的I期试验中使用的最佳剂量方案，并最终在III期关键试验中使用的信息。 这是一项开放标签，两剂量的两周，顺序跨界，药代动力学研究，将在一个研究地点在六个低肿瘤男性中进行。 在将受试者纳入研究之前，将对他们进行病史和体格检查（包括数字直肠检查）和实验室检查（完整的血液计数，临床化学，前列腺特异性抗原（PSA），激素和常规尿液分析）进行筛查。 在第一个研究期间，将要求每个受试者每天服用六剂睾丸激素棕榈酸酯每天一次（两胶囊125 mg）的研究药物。 在第二阶段，受试者将获得相同的每日总剂量；但是，它将以每天两次的疗法（早晨和晚上的125毫克胶囊）给予。 在这些研究期间，第一次剂量研究药物的早晨将接受受试者的GCRC，并将被限制在GCRC的住院单位过夜，从给药前的大约1小时，直到收集最后一个血液样本后。 受试者将在每天上午8点一次服用两次125毫克胶囊（每天250毫克）睾丸激素棕榈酸酯一次，持续6天。 T和二氢睾丸激素的血液采样（DHT，T型T）（8 mL）将在第1、6、6、15和20天收集，并在30、15和0分钟前的序列采样（0小时，8:00），然后在1、2、4、4、4、4、8、8、8、8、8、8、8、8、8、8、8、8、8、8、8、8、8、8、8、8、8、8、8、8、16、20、20、20、20、20、20和24小时和24小时。 将要求受试者在第二天（第3天）的上午8:00返回GCRC进行抽血，并在第5天的上午8:00返回。这些受试者将在第6天的早晨从剂量前1小时开始，直到收集最后一个血液样本在24小时的时间点收集最后一个血液样本。 然后，受试者将不接受任何雄激素治疗，将进行一周的洗涤期。 从第15天开始，这些受试者将在第二个研究期间返回住院GCRC。他们将仅限于第15天的30分钟，然后在给予最后一个血液样本后的GCRC住院单位过夜。 这些受试者将每天两次（在上午8点和晚上8点）服用125毫克睾丸激素的片剂，持续6天，从第15天开始。从30、15和0分钟开始收集T和DHT的血液样本（8ml），然后在早晨剂量（0小时，8:00）之前，然后在1、2、4、4、4、8、8、8、12，晚上，以后的诊所。 第17天和第19天的上午8:00，将要求受试者返回GCRC进行抽血。 抽血约为500毫升。 在四次住院研究访问中，将进行生命体征，并记录不良事件和随之而来的药物。 每个GCRC入院将进行重点进行体格检查。 安全实验室将在最后一次住院住宿中进行。 由于性交受试者可能会从T治疗中撤回长达四个星期以参加这项研究，因此在撤离期间，受试者可能会出现性功能和能量降低的症状。 从调查人员及其团队的先前经验来看，这些症状通常是温和的，直到t t t戒断后大约三周才发生。 受试者可能会受益于雄激素治疗的作用。 在给药后，预期的血清T水平将在正常成年男性中观察到的范围内。 受试者不太可能会出现任何重要的副作用，因为T是天然且已知的雄性激素。 这项研究将有助于开发一种新的口服方法，用于雄激素替代性雄激素。 长期治疗的其他可能副作用包括升高红细胞，乳房压痛，腿部肿胀，胆固醇水平的变化，前列腺大小的增加以及尿液流动的阻塞症状。 但是，由于t处理的持续时间很短，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。 不得用雄性激素治疗前列腺癌的患者。 男性将通过血清PSA水平和数字直肠检查进行筛查。