The Effect of Various Amounts of Fat on PK of Oral Testosterone Undecanoate

This is a Phase 2, open-label, randomized, cross over, pharmacokinetic study. Subjects will initially be dosed for 2 weeks (Run-In Phase) to allow suppression of endogenous testosterone production, while allowing the oral TU to reach steady state. The subjects will then be confined to a clinical unit in which they undergo the PK Phase of the study. During the PK Phase of the study, subjects will undergo a five-period cross-over in which oral TU is dosed twice daily. Subjects will dose in the morning and in the evening immediately prior to protocol-defined meals. The protocol-defined breakfasts will contain various levels of fat including 15 g, 30 g, 45 g, a breakfast consistent with the fat and calorie content of the high-fat breakfast consistent with recommendations in the Guidance for Industry on Food-Effect Bioavailability and Fed Bioequivalence Studies (December 2002), or while fasting (with no meal until 4 hours post-dose). Subjects will be randomized to a designated sequence of the protocol-defined breakfasts, or the fasted state. The subjects will be required to consume the entire breakfast within 20 minutes during the PK Phase. The protocol-defined evening meal will be required to be consumed within 20 minutes. The 5 meal periods will occur on sequential days.

Approximately twenty (20) subjects will be enrolled in order to ensure completion of 16 subjects.

Inclusion criteria

• Man 18 to 65 years of age, inclusive, with a clinical diagnosis of hypogonadism (signs/symptoms consistent with hypogonadism for testosterone naïve subjects and history of signs/symptoms for subjects who have received prior treatment) as well as testosterone levels consistent with hypogonadism as defined by 2 morning total T values of <300 ng/dL (between 6:00 and 10:00 AM drawn on 2 separate days [approximately 7 (±2) days apart].
• Adequate venous access in the left or right arm to allow collection of a number of blood samples via a venous cannula.
• Must be naïve to androgen-replacement therapy or washed out of prior androgen replacement therapies; that is, be willing to cease current T treatment or currently not be taking T treatment, (washout durations specified in exclusion criterion #1). Subjects must remain off all forms of T, except for dispensed study drug, throughout the entire study.
• Subjects on replacement therapy for hypopituitarism or multiple endocrine deficiencies must be on stable doses of thyroid hormone and adrenal replacement hormones for at least 14 days before Screen 1.
• Has voluntarily given written informed consent to participate in this study.

Exclusion criteria

• Received oral topical (eg, gel or patch), intranasal, or buccal T therapy within the previous 2 weeks, intramuscular T injection of short-acting duration (eg, T enanthate, T cypionate) within the previous 4 weeks, intramuscular T injection of long-acting duration (eg, AVEED) within the previous 20 weeks, or T implantable pellets (Testopel®) within the previous 6 months.
• Has an intercurrent disease deemed clinically significant in the opinion of the investigator of any type; in particular, liver, kidney, uncontrolled or poorly controlled heart disease, including hypertension, congestive heart failure or coronary heart disease, or psychiatric-illness, including severe depression.
• Has had a recent (within 2 years) history of stroke, transient ischemic attack, or acute coronary event.
• Has a mean of the triplicate assessment of sBP > 150 mm Hg and/or dBP > 90 mm Hg at screening (if prescribed antihypertensives, subject should be taking medications on the day of the screening visit with a sip of water). Subjects < 60 years of age and prescribed antihypertensives will be excluded if the mean of the triplicate assessment of sBP > 140 mm Hg and/or dBP > 90 mm Hg at screening.
• Has had recent (within 2 years) history of angina or stent (coronary or carotid) placement.
• Has untreated, severe obstructive sleep apnea.
• Has clinically significant abnormal laboratory values, including serum transaminases > 2 × upper limits of normal (ULN), serum bilirubin > 1.5 × ULN and serum creatinine > 1.5 × ULN.
• Has a hematocrit (HCT) value of < 35% or > 48%.
• Has a history of polycythemia, either idiopathic or associated with TRT treatment.
• Is a diabetic subject with a glycosylated hemoglobin > 8.5%.
• Has a body mass index (BMI) ≥ 38 kg/m2.
• Has been on stable doses of antihypertensive medication for < 3 months.
• Has an abnormal prostate digital rectal examination [(DRE); palpable nodules], elevated PSA (serum PSA > 4.0 ng/mL), I-PSS > 19 points at screening, and/or history of, or current or suspected, prostate cancer.
• Has a history of, or current or suspected, breast cancer.
• Has a history of abnormal bleeding tendencies or thrombophlebitis unrelated to venipuncture or intravenous cannulation within the previous 2 years.
• Use of dietary supplements such as saw palmetto or phytoestrogens and any dietary supplements that may increase total T, such as androstenedione or dehydroepiandrosterone within the previous 4 weeks.
• Has known malabsorption syndrome and/or current treatment with oral lipase inhibitors (eg, orlistat [Xenical®]) and/or bile acid-binding resins (eg, cholestyramine [Questran®], colestipol [Colestid®]) or treatments that promote gastric emptying (eg, metoclopramide [Reglan®]).
• Inability to observe all rules and smoking restrictions in place at the clinical facility during confinement.
• Has history of abuse of alcohol or any drug substance within the previous 2 years.
• Poor compliance or unlikely to keep clinic appointments and remain for entire confinement period.
• Has received any drug as part of another research study within 30 days of initial dose administration in this study.
• Donated blood (≥ 500 mL) within the 12-week period before the initial study dose.
• Current use of the following groups of drugs that effect T levels, T metabolism or levels of T metabolites, namely antiandrogens, 5-alpha-reductase inhibitors (eg, dutasteride, finasteride), estrogens, long-acting opioid analgesics (eg, methadone hydrochloride, buprenorphine hydrochloride) or human growth hormone (HGH).
• Unwilling or unable to follow the dietary requirements for this study.