Reexamination of Pharmacokinetics of Oral Testosterone Undecanoate in Hypogonadal Men With a New Self-Emulsifying Formulation

Department of Medicine, Division of Endocrinology, Harbor-UCLA Medical Center, Torrance, California, USA.
Journal of Andrology (Impact Factor: 2.47). 04/2011; 33(2):190-201. DOI: 10.2164/jandrol.111.013169
Source: PubMed


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.

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    • "The increased lipophilicity of TU relative to other TEs, affords increased absorption by the intestinal lymphatic system without the well characterized overt hepatotoxicity associated with orally administered 17-alkylated androgens such as methyl T.3435 Consistent therapeutic levels of T are often challenging to achieve following oral TU administration. Despite an improved formulation, 300 mg twice daily dosing of TU, or roughly 50 molar equivalents of the T generated daily by healthy testes, is required to maintain physiological nadir levels of serum T. The risk associated with the super physiological serum 5α-dihydrotestosterone (DHT) levels and increased androgen burden on the liver that result from this dosing regimen are disputed.35 However, the reduced utilization of oral TU relative to the multiple parenteral T formulations available suggests that the perceived risks outweigh the convenience of an oral dosage form in the minds of patients and their physicians. "
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    ABSTRACT: Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism. Selective androgen receptor modulators (SARMs) have been shown to provide anabolic benefit in the absence of androgenic effects on prostate, hair and skin. Current clinical development for SARMs is focused on acute muscle wasting conditions with defi ned clinical endpoints of physical function and lean body mass. Similar regulatory clarity concerning clinical deficits in men with hypogonadism is required before the beneficial pharmacology and desirable pharmacokinetics of SARMs can be employed in the treatment of late onset male hypogonadism.
    Full-text · Article · Dec 2013 · Asian Journal of Andrology
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    • "The reference range for normal serum T is 10.4 to 34.7 nmol/L (300 to 1000 ng/dL, based on regulatory guidelines from the Food and Drug Administration and similar to the laboratory reference ranges in adult men); for DHT the normal reference range is 0.47 to 2.7 nmol/L (13.7 to 77 ng/dL, determined in our laboratory from 113 healthy adult men). Serum TU and DHTU were measured by LC-MS/MS without modification as previously described (Yin et al, 2011). "
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    ABSTRACT: Introduction This study investigates the effect of dietary fat on the testosterone (T) pharmacokinetics (PK) in hypogonadal men following administration of a self-emulsifying capsule formulation of oral testosterone undecanoate (TU). Subject and Methods: In an open-label, two-center, five-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 five days between doses. All subjects 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 pre-dose to 25 hours post-dose to determine serum T and dihydrotestosterone (DHT) by liquid chromatography tandem mass spectrometry (LC-MS/MS). Results: 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 (Cavg) and peak serum T concentrations (Cmax) and area under the curve (AUC) 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%-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. Conclusions: As expected with the maximum anticipated clinical dose of TU (300 mg), 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 (10-35 nmol/L).
    Full-text · Article · Jul 2012 · Journal of Andrology
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    ABSTRACT: Although testosterone has been in clinical use for almost 70 years, it has only slowly attracted interest from clinical researchers. This is partly due to the fact that hypogonadal men requiring testosterone treatment constitute only a minority of all patients, and hypogonadism is not a life-threatening disease. Since development of new preparations is mainly a task of the pharmaceutical industry, and hypogonadal patients did not promise to contribute a substantial economic profit, development of testosterone preparations was slow. Only recently has the question of testosterone treatment of senescent men (see Chapter 16) and, to a certain extent, also the search for a hormonal male contraceptive (see Chapter 22) spurred interest in the pharmacology and application of testosterone. Today oral, buccal, injectable, implantable and transdermal testosterone preparations are available for clinical use. There are only a few, especially few not-industry-sponsored, clinical studies available comparing the various preparations with the goal of identifying the optimal preparation for substitution purposes. While the older injectable testosterone preparations produce supraphysiological serum testosterone levels, newer preparations achieve levels closer to the physiological range. We are only beginning to understand which serum levels are required to achieve the various biological effects of testosterone and to avoid adverse side-effects. In particular, very little is known about long-term effects of testosterone therapy inherent to different preparations. Similarly, the role of the AR polymorphism in modifying testosterone action individually is becoming understood only slowly, but may lead to a pharmacogenetic concept for the therapeutic application of testosterone (Zitzmann 2009; see also Chapter 3).
    No preview · Article · Jan 2012
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