JATENZO®: Challenges in the development of oral testosterone

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madman

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Testosterone therapy (TT) for the treatment of testosterone deficiency (TD) can be administered via several routes of administration. Due to a variety of concerns such as hepatotoxicity, an oral formulation has long been absent in the United States. Recently, JATENZO® (testosterone undecanoate) oral capsules were approved by the US FDA as an oral option for men suffering from TD. In this article, we will discuss the history and challenges in the development of a viable oral formulation of exogeneous TT and examine how JATENZO® addresses these concerns.




INTRODUCTION

Testosterone deficiency (TD) is defined as having low serum testosterone in addition to clinical signs and symptoms of low testosterone. As the primary male sex hormone, testosterone plays an integral role in homeostasis with low serum levels often manifesting as fatigue, low libido, poor muscle mass, and osteoporosis [1–5]. Testosterone therapy (TT) attempts to treat TD with the goals of improving symptoms and increasing serum testosterone to physiologic levels in the range of 450–600 ng/dL [6]. Multiple population-based studies have demonstrated an overall prevalence of TD of 6%, an estimate that significantly increases as men age [7–9]. A recent study also demonstrated that rates among young males and adolescents are rising over time, possibly indicating that this disease process may become even more common [10]. The burdensome symptoms and high prevalence among the general population render TD a commonly encountered problem for physicians.

The number of TT prescriptions has dramatically increased in the United States over time [11], has sparked interested in developing easier to use, better-tolerated formulations. Physicians now have a plethora of options to offer patients with various routes of administration including intranasal, buccal, intramuscular, and subcutaneous injections, transdermal gels and patches, and pellet implants, each of which has unique advantages and disadvantages (Table 1). Until recently, however, physicians lacked FDA-approved oral options to offer patients. Oral formulations of testosterone are convenient, easy to use, and avoid common problems of other TT such as painful injections, rashes, nasal symptoms, and transference to women and children. In other disease processes such as rheumatoid arthritis and multiple sclerosis, studies have suggested patients prefer oral medications over other formulations with improved adherence, quality of life, and patient satisfaction [12, 13].

Oral testosterone has long been sought after as a viable option for patients, yet has been difficult to obtain.
Recently approved in 2019, JATENZO® (Clarus Therapeutics, Northbrook, IL, USA) is one of the only FDA-approved oral testosterone agents. Here, we review the history of the development of oral testosterone, the current landscape of oral testosterone, and how JATENZO® addresses the concerns of prior oral options.




*PHARMACOLOGY OF ORAL TESTOSTERONE THERAPY

Oral administration of exogenous TT historically has proven to be unsuccessful. Despite adequate absorption in the gastrointestinal system, this form of testosterone undergoes extensive first-pass metabolism through the liver, and thus requires ingestion of supraphysiological doses to attain therapeutic serum levels [14]. As a way to circumvent the liver metabolism pathway, research efforts to administer oral testosterone have taken two primary paths: alkylation of testosterone at the carbon-17 position and fatty-acid esterification of testosterone to create a testosterone ester (Fig. 1).

Alkylation of testosterone at carbon 17α results in 17αmethyltestosterone which allows for the ability to bypass the first metabolism in the liver. However, this modification has been linked to significant liver toxicity including cholestasis, hepatitis, and hepatic adenocarcinoma [15–17] and lowering of HDL cholesterol [18, 19]. The effects of methyltestosterone on liver function were first described in the 1940s, with studies of liver function demonstrating elevations in both serum direct and indirect bilirubin levels [19]. Foss and Simpson also described a case series of 42 patients who developed jaundice during methyltestosterone therapy [20]. They noted that the duration of therapy to the onset of jaundice ranged from 8 days to 10 months and withdrawal of methyltestosterone therapy resulted in remission of hepatocellular dysfunction within a few days to weeks. Recent work has focused on testing the effects of synthetic androgens on liver function utilizing animal models [21] and has corroborated prior work demonstrating direct increases in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and sorbitol dehydrogenase. Therefore, methyltestosterone is largely not recommended for the management of male hypogonadism [6, 22].

Esterification of testosterone at carbon 17β yields testosterone esters such as testosterone cypionate, testosterone propionate, and testosterone undecanoate (TU). Specifically for TU, this modification allows testosterone to be absorbed via the lymphatic system and therefore bypass liver degradation. An early oral TU formulation (ANDRIOL®) was approved for use in many countries but never in the United States. This formulation is heavily reliant on dietary fat intake as a means of increasing absorption and therefore leads to significant intra- and inter-patient variability in testosterone response [23, 24]. This results in the need to dose hypogonadal men with several capsules three or more times daily affecting compliance. Several studies have also demonstrated both gastrointestinal and liver adverse effects including severe cholestasis and jaundice [25, 26]. Consequently, these oral TU formulations have never been widely utilized to treat TD in the United States although they remain available in many countries



*SELF-EMULSIFYING DRUG DELIVERY SYSTEM (SEDDS)

TU has been formulated in a unique self-emulsifying drug delivery system (SEDDS) that was initially evaluated in multi-institutional placebo-controlled studies in Europe [27]. SEDDS formulations combine hydrophilic and lipophilic components that enable the solubilization of lipophilic molecules such as TU in the gut (Fig. 2). This promotes intestinal lymphatic absorption of lipophilic testosterone esters, thereby reducing first-pass hepatic metabolism. Furthermore, this formulation allows absorption after oral ingestion with a typical meal as opposed to high-fat content meals required for prior formulations. Yin et al. showed that this TU with SEDDS resulted in adequate serum testosterone levels within the physiologic range after dosing with just TU 200 mg twice per day in most hypogonadal men [28].


*JATENZO®
 

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madman

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Table 1. Advantages and disadvantages of the various formulations of testosterone preparations.
Screenshot (7505).png
 

madman

Super Moderator
Fig. 1 Molecular structure of testosterone with modifications to improve the tolerability of oral formulations. A Testosterone B 17αmethyltestosterone C Testosterone undecanoate.
Screenshot (7506).png
 

madman

Super Moderator
Fig. 2 Pictorial representation of TU lymphatic absorption after oral delivery in SEDDS formulation. Reprinted from Swerdloff et al., 2020 [29] with permission from SAGE Publishing.
Screenshot (7507).png
 
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