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

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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.