Dietary Fat Modulates the Testosterone Pharmacokinetics of a New Self‐Emulsifying Formulation of Oral Testosterone Undecanoate in Hypogonadal Men

Abstract

This study investigates the effect of dietary fat on the testosterone (T) pharmacokinetics in hypogonadal men following administration of a self-emulsifying capsule formulation of oral T undecanoate (TU). In an open-label, 2-center, 5-way crossover study, a single oral dose of TU containing 300-mg equivalents of T (maximum anticipated human dose per administration) was administered to 16 hypogonadal men with a washout period of at least 5 days between doses. All participants were randomized to receive the TU capsules fasting or 30 minutes after an approximately 800-calorie meal containing 10%, 20%, 30%, or 50% fat. Serial blood samples were collected from 2 hours predose to 25 hours postdose to determine serum T and dihydrotestosterone (DHT) by liquid chromatography tandem mass spectrometry. Administering TU with a meal increased serum T concentrations, with the magnitude of the increase being directly dependent on the amount of fat in the meal. Average and peak serum T concentrations and area under the curve increased as the fat content of the meal was increased. Neither the high-fat meal (50% fat) nor the lower-fat meal (20% fat) showed a significant food effect relative to the normal-fat (Western diet) meal (30% fat). However, administering TU while fasting resulted in 50% or less of the cumulative exposure obtained when administered with 20%- to 50%-fat meals (albeit still substantial). A very-low-fat meal (10% fat) showed a significant food effect relative to the normal meal, but still exceeded the fasting condition by approximately 50%. Serum DHT concentrations showed corresponding increases to the serum T. As expected with the maximum anticipated clinical dose of TU (300 mg T), oral administration of this new formulation with food containing 20% to 50% dietary fat produced T levels at or above the upper range of adult men, and T levels trended higher as dietary fat content increased. Only with a very-low-fat diet (10%) or in a fasted state did a clinically significant food effect occur, but even then sufficient TU was absorbed with the self-emulsifying TU formulation to produce average serum T concentration predicted to be in the normal reference range (10 to 35 nmol/L).

Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive

“…Studies of TU in oleic acid, castor oil or as a Self-Emulsifying Drug Delivery System (SEDDS) formulations have demonstrated that administration of TU with a fatty meal compared to fasting increased serum T and DHT levels (Bagchus, et al , 2003; Schnabel, et al , 2007; Yin, et al , 2012; Yin, et al , 2012). In our study, peak levels of DMA were reached at 4 to 6 hours after ingestion with food, similar to TU in oil or SEDDS administered with a high fat diet (Yin, et al , 2012). TU is absorbed mainly through the intestinal lymphatics because the aliphatic undecanoate ester chain allows TU to travel with dietary lipids in the lymphatics (Horst, et al , 1976; Shackleford, et al , 2003).…”

“…Oral TU in castor oil (Andriol Testocap®), when administered to dogs, gave equivalent concentrations of TU and T measured in thoracic duct lymphatics suggesting complete hydrolysis of the TU to T in the systemic circulation (Shackleford, et al , 2003). Oral TU administered as a SEDDS formulation with food resulted in serum concentrations of T was about 30 percent of serum concentration of TU (Yin, et al , 2012). From these studies in dogs and men, the undecanoate moiety from oral TU in castor oil or SEDDS appears to release T from TU in the body rapidly and much more efficiently than DMAU conversion to DMA when DMAU is administered as a powder in capsules.…”

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].…”

Current topics in testosterone replacement of hypogonadal men

“…Long-term use is safe, as has been demonstrated in a 10-year observation study [42]. The same impact of an accompanying meal, especially containing fat, can be observed with a new selfemulsifying testosterone undecanoate preparation given in 300 mg capsules [43]. With one daily dose this preparation shows more stable testosterone kinetics.…”