An oral lipidic native testosterone formulation that is absorbed independent of food

Context

There is no licensed oral native testosterone (NT) because of challenges in the formulation. Licensed oral formulations of the ester, testosterone undecanoate (TU), require a meal for absorption and generate supraphysiological dihydrotestosterone (DHT) levels.

Objective

To develop an oral NT formulation.

Design and methods

A lipid-based formulation of native testosterone filled into soft-gelatin capsules at 40 mg per capsule was designed with 2 years of stability at ambient temperature. Pharmacokinetic comparison studies of this oral lipidic NT formulation to oral TU were conducted in dogs and hypogonadal men.

Results

In dogs, 40 mg NT was well absorbed under fasted conditions whereas 40 mg TU required a high-fat meal: for NT, the mean fed/fasted AUC ratio was 1.63 and for TU 7.05. In hypogonadal men, fed and fasted NT had similar pharmacokinetics: C_max mean 26.5 vs 30.4 nmol/L (769 vs 882 ng/dL), AUC_{0–10 h} 87 vs 88.6 h nmol/L. NT (fed state) showed a testosterone AUC increase of 45% between 120 and 200 mg, and NT 200 mg gave a similar mean AUC_{0–10 h} to TU 80 mg: 87 vs 64.8 h nmol/L. Serum TU levels were variable and on a molar basis were ~ten-fold higher than serum testosterone levels after TU 80 mg fed. The DHT: testosterone AUC_{0–10 h} ratio was more physiological for NT than TU being 0.19 vs 0.36. There were no emerging safety concerns with NT.

Conclusion

This novel oral lipidic native testosterone formulation has potential advantages over oral TU of dosing independently of food and a lower risk of supraphysiological DHT levels.

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Article information: Newell-Price, J., Huatan, H., Quirke, J., Porter, J., Daniel, E., Mumdzic, E., Voet, B., Keevil, B., Whitaker, M. J., & Ross, R. J. (2021). An oral lipidic native testosterone formulation that is absorbed independent of food, European Journal of Endocrinology, 185(5), 607-615. Retrieved Oct 11, 2021