Important Effect of Food on the Bioavailability of Oral Testosterone Undecanoate

Wilma M. Bagchus, Ph.D., Rita Hust, M.D., Frans Maris, Ph.D., Peter G. Schnabel, M.S., Natalie S. Houwing, M.S.


Pharmacotherapy. 2003;23(3) 

In This Article

Abstract and Introduction

Study Objective: To assess the effects of food on the bioavailability of testosterone undecanoate, testosterone, and 5 -dihydrotestosterone (DHT) after administration of a new oral testosterone undecanoate formulation, Andriol Testocaps.
Design: Randomized, open-label, crossover study with a 1-week washout period.
Setting: Clinical pharmacology unit.
Subjects: Sixteen healthy postmenopausal women.
Intervention: Single oral doses of testosterone undecanoate 80 mg were administered either during a fasting period or after consumption of a standardized continental breakfast.
Measurements and Main Results: Serum concentrations of testosterone undecanoate were assayed by liquid chromatography with mass spectrometry detection; testosterone and DHT were assayed by gas chromatography with mass spectrometry detection. Serum concentrations of testosterone, testosterone undecanoate, and DHT were low to negligible when testosterone undecanoate was administered to subjects in a fasting state; these values were significantly higher when the test drug was coadministered with food. For testosterone, the maximum serum concentration and area under the plasma concentration-time curve were 0.67 ng/ml and 5.37 ng·hr/ml, respectively, in the fasting state, versus 10.7 ng/ml and 56.4 ng·hr/ml, respectively, in the fed state. The same parameters were also significantly higher for testosterone undecanoate and DHT in the fed versus fasting subjects.
Conclusion: Food increases the bioavailability of testosterone undecanoate, testosterone, and DHT. For proper absorption, Andriol Testocaps must be taken with meals.

Testosterone replacement therapy is administered in a wide range of circumstances. It restores natural androgen levels in patients with primary or secondary hypogonadal disorders, whether congenital or acquired, as occurs after castration or with eunuchoidism, hypopituitarism, endocrine impotence, and certain types of infertility. It is used to treat symptoms of partial androgen deficiency in aging men (andropause); these symptoms include depressed mood, fatigue, loss of energy, sexual problems, and problems with physical agility. Testosterone is given to female-to-male transsexuals to induce masculinization, and it is used to treat osteoporosis caused by androgen deficiency.[1]

Oral administration of testosterone results in low bioavailability due to presystemic clearance by the liver. To circumvent this first-pass effect in the liver, testosterone sometimes is administered in patches, gels, injections, or implants. Another option is Andriol (Organon, Oss, The Netherlands), the only oral testosterone formulation, designed to deliver testosterone to the systemic circulation by the intestinal lymphatic route, thereby circumventing first-pass inactivation in the liver. Andriol, which is available in more than 80 countries, contains testosterone undecanoate dissolved in oleic acid inside a soft gelatin capsule. The esterification of testosterone with undecanoate renders testosterone undecanoate sufficiently lipophilic to be incorporated in chylomicrons formed during lipid digestion in the intestine. These chylomicrons then are transported by the intestinal lymphatic system. Another factor that is relevant to the extent of lymphatic absorption is the nature of the lipophilic solvent in the capsule.[2,3]

During absorption, testosterone undecanoate is partly reduced to 5 -dihydrotestosterone undecanoate (DHTU), which also is absorbed by the lymphatic system.[4] From the lymphatic system, testosterone undecanoate and DHTU are released into the circulation by the thoracic duct. Both testosterone undecanoate and DHTU are hydrolyzed to yield the natural male androgens, testosterone and 5 -dihydrotestosterone (DHT).[4,5] Because of this lipid-associated route of absorption, one would expect that administration of oral testosterone undecanoate with a meal would enhance absorption and thus increase the bioavailability of testosterone undecanoate, testosterone, and DHT. The enhancing effects of food on the lymphatic absorption of lipophilic compounds have been confirmed in a dog model using halofantrine[6] and in humans with an experimental oral testosterone undecanoate formulation.[7] Although the relevance of food to the bioavailability of testosterone undecanoate is acknowledged in the product labeling, no detailed clinical study had yet been conducted.

Andriol must be stored in a refrigerator (2-8°C) in the pharmacy for stability reasons, whereas patients must store it at room temperature to ensure optimal absorption. Shelf-life at room temperature is only 3 months. These complicated storage requirements carry the risk of nonadherence, which might result in administration of inactive compound. Therefore, a new, more stable pharmaceutical formulation of Andriol -- Andriol Testocaps (Organon) -- was developed in which the oleic acid solvent is replaced by castor oil and propylene glycol laurate. The improved formulation can be stored at room temperature (15-30°C) for 3 years.

This study evaluated serum concentrations of testosterone undecanoate, testosterone, and DHT, with the goal of assessing the effects of a standardized meal on the pharmacokinetic properties of a single oral dose of testosterone undecanoate 80 mg in the form of Andriol Testocaps.