A New Oral Testosterone Undecanoate Formulation Restores Testosterone to Normal Concentrations in Hypogonadal Men

Ronald S. Swerdloff; Christina Wang; William B. White; Jed Kaminetsky; Marc C. Gittelman; James A. Longstreth; Robert E. Dudley; Theodore M. Danoff

Disclosures

J Clin Endocrinol Metab. 2020;105(8) 

In This Article

Abstract and Introduction

Abstract

Context: A novel formulation of oral testosterone (T) undecanoate (TU) was evaluated in a phase 3 clinical trial.

Objective: Determine efficacy, short-term safety, and alignment of new oral TU formulation with current US approval standards for T replacement therapy.

Design: Randomized, active-controlled, open-label study.

Setting and Patients: Academic and private clinical practice sites; enrolled patients were clinically hypogonadal men 18 to 65 years old.

Methods: Patients were randomized 3:1 to oral TU, as prescribed (JATENZO®; n = 166) or a topical T product once daily (Axiron®; n = 56) for 3 to 4 months. Dose titration was based on average T levels (Cavg) calculated from serial pharmacokinetic (PK) samples. T was assayed by liquid chromatography–mass spectrometry/mass spectrometry. Patients had 2 dose adjustment opportunities prior to final PK visit. Safety was assessed by standard clinical measures, including ambulatory blood pressure (BP).

Results: 87% of patients in both groups achieved mean T Cavg in the eugonadal range. Sodium fluoride-ethylenediamine tetra-acetate plasma T Cavg (mean ± standard deviation) for the oral TU group was 403 ± 128 ng/dL (~14 ± 4 nmol/L); serum T equivalent, ~489 ± 155 ng/dL (17 ± 5 nmol/L); and topical T, 391 ± 140 ng/dL (~14 ± 5 nmol/L). Modeling/simulation of T PK data demonstrated that dose titration based on a single blood sample 4 to 6 h after oral TU dose yielded efficacy (93%) equivalent to Cavg-based titration (87%). Safety profiles were similar in both groups, but oral TU was associated with a mean increase in systolic BP of 3 to 5 mm Hg.

Conclusion: A new oral TU formulation effectively restored T to mid-eugonadal levels in hypogonadal patients.

Introduction

Male hypogonadism, or androgen deficiency, is diagnosed when unequivocally low serum testosterone (T) levels [typically <300 ng/dL (~10 nmol/L)] and consistent signs and symptoms are present.[1] Regardless of the etiology, several signs and symptoms often can be managed with exogenous T replacement.[2]

Testosterone replacement therapy (TRT) is administered by various delivery routes including transdermal gels and lotions; intramuscular and subcutaneous injections; surgically implanted pellets; dermal patches; intranasal gels; and oral capsules and tablets (methyltestosterone). Each of these delivery routes are associated with drawbacks well known to healthcare practitioners (HCP) and their patients [e.g., pain of injection, dermal irritation, T transference and liver toxicity (oral methyltestosterone)]. What has been absent from the HCP's armamentarium of TRT products in the U. S. is an oral T formulation that meets current regulatory standards for safety and efficacy [e.g., FDA requires average serum T concentrations in the eugonadal range of 300–1000 ng/dL (10–35 nmol/L) for at least 75% of treated men with peak T concentrations largely below 1500 ng/dL (52 nmol/L)]. Historically, efforts to administer oral T have taken two primary paths: alkylation of T at the C-17 position to create T analogs that are resistant to first pass hepatic metabolism (exemplified by methyltestosterone dating to 1935 when first synthesized and used clinically by Ruzika);[3] or fatty acid esterification of T to create a T-ester [exemplified by T-undecanoate (TU)] that is absorbed via the intestinal lymphatic system thus bypassing the portal circulation.[4] Oral methyltestosterone has been associated with serious hepatotoxicity such as cholestasis, peliosis hepatis, and hepatic adenocarcinoma[5–8] and therefore is rarely used in the clinical management of male hypogonadism. Conversely, while oral TU has not been associated with liver toxicity, an early oral TU formulation approved for use in many countries (but never in the U. S.) was highly influenced by dietary fat, thus leading to significant intra- and inter-patient variability in T response and questionable clinical utility.[9,10] Reformulation of this product to reduce the effect of dietary fat did not address the low TU content of the capsules thus resulting in the need to dose hypogonadal men with several capsules three or more times daily. Even then, reported serum T response would not result in average serum T levels in the normal range or meet current FDA efficacy standards.[11] Accordingly, neither of these oral formulations has enjoyed widespread clinical use to treat T deficiency.

To address the absence of an oral TRT product that meets the rigor of current-day U. S. regulatory requirements for efficacy and safety, TU was formulated in a unique self-emulsifying drug delivery system that was initially evaluated in short-term clinical studies.[12] In brief, the specific formulation we evaluated (encapsulated in soft gelatin capsules of various strengths) consisted of TU dissolved in a combination of lipids (principally long-chain fatty acids; e.g., oleic acid) and other solubilizers [e.g., borage seed oil (a rich source of C-20 fatty acids) and peppermint oil)] and a hydrophilic surfactant [hydrogenated castor oil (Cremophor® RH 40)]. Formulations of this type enable the solubilization of highly lipophilic molecules like TU so that they may be absorbed after oral ingestion with food (high fat content not required).[13] Systemic delivery of oral TU occurs almost exclusively (>97%) via the intestinal lymphatic system, thereby bypassing the liver.[4,14] Once in the circulation, T is liberated from TU via the action of endogenous non-specific esterases. The undecanoic side chain (a C-11 fatty acid) is pharmacologically inert and metabolized by β-oxidation to acetyl coenzyme A (CoA) and, in the final step, propionyl CoA. Notably, during development of this new oral TU formulation, it became clear that enzymatic cleavage of T from TU can also occur during the standard laboratory processing of blood drawn from men treated with oral TU. The consequence of this post collection production of T was that assayed T values did not accurately reflect the actual circulating T concentration [i.e., they were artefactually high[15,16]]. Therefore, in the pivotal clinical trial described herein, post-collection conversion of TU to T was minimized in men dosed with oral TU by assaying for T in plasma derived from blood collected into NaF-EDTA tubes that were held on ice prior to centrifugation (a process that halts all TU to T conversion). Because this sample handling approach is not typical in clinical practice, the dose titration algorithm utilized in the present trial (based on T measurements in NaF-EDTA plasma) was adapted for use with a single serum sample derived from blood collected into a standard plain collection tube (i.e., without added chemicals).

The present study was designed to assess the efficacy, based on T response and various patient-reported outcomes, and safety of a new oral TU formulation (JATENZO®) developed to treat male hypogonadism. In addition to standard safety assessments, we evaluated the potential impact of oral TU therapy on adrenal function and 24-hour ambulatory blood pressure. Finally, the effect of dietary fat content on T levels after oral TU administration was evaluated to determine if this was an important factor for T response.

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