Reexamination of pharmacokinetics of oral testosterone undecanoate in hypogonadal men with a new self-emulsifying formulation

Abstract

Many hypogonadal men prefer oral testosterone (T) treatment. Oral T undecanoate (TU) is available in many countries, but not in the United States. We aimed to assess the pharmacokinetics of oral TU in a new self-emulsifying drug delivery system formulation. Pharmacokinetics studies were conducted in 3 parts: 12 hypogonadal men were enrolled in 2 centers for a 1-day dosing study; 29 participants were enrolled from 3 centers for a 7-day dosing study; and 15 participants were enrolled from 1 center for a 28-day dosing study. Serial blood samples for serum sex hormone measurements by liquid chromatography-tandem mass spectrometry were drawn for up to 36 hours after oral TU administration. Mean serum T levels (C(avg)) after oral dosing of T 200 mg as TU twice daily with food were within the adult male range in most participants in the 1-, 7-, and 28-day dosing studies but were much lower in the fasting state. The dose-proportional increase in C(avg) of serum T after oral T 300 mg twice daily resulted in more participants with supraphysiologic serum T levels. In the 28-day study, trough serum T reached a steady state at day 7. Serum dihydrotestosterone and estradiol levels tracked serum T concentration. Dihydrotestosterone-testosterone ratios increased 3-fold after oral TU administration. Oral T 200 mg twice daily as TU in a new SEDDS formulation may be a viable therapy for hypogonadal men.

Trial registration: ClinicalTrials.gov NCT00695110 NCT00911586.

Figure 1

Serum testosterone (T) (A, B, C) and dihydrotestosterone (DHT) (D, E, F) concentrations after a single-day oral dose of T 100 mg twice a day (BID) (A, D), 200 mg once (B, E), and 200 mg twice a day (C, F) as oral testosterone undecanoate (TU; geometric mean ± SEM).

Figure 2

Serum testosterone (T) (A), dihydrotestosterone (DHT) (B), and DHT/T (C) on day 7 after T 300 mg as oral testosterone undecanoate administered twice a day for 7 days (geometric mean ± SEM).

Figure 3

Serum testosterone (T) (A, B), dihydrotestosterone (DHT) (C, D), testosterone undecanoate (TU) (E, F), and dihydrotestosterone undecanoate (DHTU) (G, H) concentrations on day 7 after T 200 mg twice a day (BID) as oral TU for 6 consecutive days (geometric mean ± SEM). A single dose of TU was administered on day 7 after food (right panels) and on day 8 in the fasting state (left panels).

Figure 4

Serum testosterone (T), dihydrotestosterone (DHT), DHT/T, estradiol (E2), and E2/T trough concentrations (geometric mean ± SEM) during and after T 200 mg twice a day as oral testosterone undecanoate for 28 days.

Figure 5

Serum testosterone (T) (A), dihydrotestosterone (DHT) (B), estradiol (E2) (C), and DHT/T (D) concentrations (geometric mean ± SEM) after the last dose of oral T 200 mg twice a day as oral testosterone undecanoate administered for 28 days.