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Nanomilled Oral Testosterone Plus Dutasteride Effectively Normalizes Serum Testosterone in Normal Men With Induced Hypogonadism

RICHARD V. CLARK

MARK A. BUSH

HUI ZHI

RALPH B. CARICOFE

PETER M. SMITH

From the ^* Center for Research in Reproduction and Contraception, Divisions of General Internal Medicine and Endocrinology, Metabolism, and Nutrition, Department of Medicine, University of Washington Medical School, Seattle, Washington; and GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina.

Correspondence to: Stephanie T. Page, University of Washington, Box 356138, 1959 NE Pacific St, Seattle, WA 98195 (e-mail: page{at}u.washington.edu).

Oral androgen development has been hampered by the rapid metabolism of orally administered testosterone (T) and low bioavailibility. The addition of the 5-reductase inhibitor dutasteride (D) to oral T in oil dramatically improves concentrations of serum T. In this study we evaluate the absorption of oral T+D, comparing nanomilled T (NmT+D) vs T dissolved in oil (Capmul; CpT+D), as nanomilling might offer a simpler, more practical means of oral T administration, given the limited solubility of T in oil. Twelve healthy men were administered leuprolide on Day –14 to suppress endogenous T biosynthesis and were pretreated with D to block 5-reductase. Once hypogonadal, subjects were sequentially administered 200- and 400-mg doses of CpT+D and NmT+D in the fasted and fed states. Serum T and dihydrotestosterone (DHT) were measured: before dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after each dose. Two weeks after leuprolide administration, T levels were below the normal range. A 400-mg dose of either formulation of oral T+D increased mean serum T above the lower limit of the normal range for 8–10 hours. Food had a minimal effect on the pharmacokinetic parameters of the NmT+D formulation but decreased the maximum observed concentration after dosing (C_max) for CpT+D. Serum DHT remained below the normal range throughout the study period with both formulations. No significant changes in liver function tests or other adverse events were observed. A 400-mg dose of either oral T+D formulation normalized serum T for 8–10 hours and suppressed DHT. NmT allows for tablet formulation, and its pharmacokinetics were not affected by food, demonstrating the feasibility of oral nanomilled T as a promising and practical twice-daily therapy for the treatment of male hypogonadism.

     Key words: Androgen, 5-reductase