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 (Cavg) 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 Cavg 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.

An update on male hypogonadism therapy

“…An oral TU with a proprietary Self Emulsifying Drug Delivery System is being evaluated at higher doses than oral TU in castor oil. Significantly higher serum testosterone levels are attained with the new formulation and food intake improves the absorption [133,134]. Because of the presence of 5 α reductase enzyme in the gut and conversion of the administered TU to DHT TU, serum DHT to testosterone levels may be slightly higher than other testosterone preparations [134].…”

“…Significantly higher serum testosterone levels are attained with the new formulation and food intake improves the absorption [133,134]. Because of the presence of 5 α reductase enzyme in the gut and conversion of the administered TU to DHT TU, serum DHT to testosterone levels may be slightly higher than other testosterone preparations [134]. Pivotal Phase III trials have been completed and if it receives FDA approval, it will be the first oral TU available in the US.…”

Efficacious Intestinal Permeation Enhancement Induced by the Sodium Salt of 10-undecylenic Acid, A Medium Chain Fatty Acid Derivative

“…The terminal alkene of uC 11 reduces its hydrophobicity compared to the saturated C 11 salt, with a resultant increase in solubility and critical micelle concentration (CMC) (15,16). UA and its salts have been used as penetration enhancers in transdermal drug delivery (17,18), and there have been attempts to improve oral delivery of testosterone using a UA ester (19,20); however, the use of either UA and/or uC 11 specifically as intestinal permeation enhancers has never been investigated. uC 11 is a powder, more amenable to commercial-scale solid dose manufacturing than the acid form and was therefore more appropriate for the current oral drug delivery study.…”

Importance of Measuring Testosterone in Enzyme-Inhibited Plasma for Oral Testosterone Undecanoate Androgen Replacement Therapy Clinical Trials

“…Testosterone undecanoate (TU), a prodrug of testosterone (T) is metabolized by nonspecific esterases in blood to testosterone [1,2]. More specifically, TU is metabolized partly in the intestinal wall into 5-alpha-dihydrotestosterone undecanoate (DHTU).…”

“…To minimize conversion of TU to testosterone during the preparation of serum from blood, published literature in preclinical studies of TU has reported the use of potassium fluoride in sample collection tubes [8]. However, published clinical data on TU have used standard serum tubes without an esterase inhibitor [2–7]. One publication on the validation of a bioanalytical method for testosterone analysis concluded that TU is stable in blood [9].…”