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

Discussion

This multicenter, Phase 3 study in adult hypogonadal men was designed to evaluate the efficacy and safety of oral TU to support U. S. regulatory approval. The primary goal of T therapy in hypogonadal men is to achieve mean daily T levels the eugonadal range, avoid excessive peak concentrations,[26] and ameliorate symptoms associated with T deficiency. Oral TU restored T to eugonadal levels in 87.3% of patients with an approximate mean serum T Cavg of 489 ± 155 ng/dL (converted from NaF-EDTA plasma T values) and with a mean Cmax response that was in close alignment with FDA targets established for TRT products. In addition, oral TU was associated with clinically significant improvements in symptom relief. The overall safety profile of oral TU was like that for other approved TRT products and reflected the well-recognized adverse effect profile of TRT products as a class (e.g., decreased HDL, increased hematocrit). However, oral TU was associated with a modest mean increase in systolic blood pressure of 3 5 mmHg. As expected, patients treated with oral TU experienced a greater number of GI-associated side effects [e.g., nausea, diarrhea, and burping (often described as 'minty burps' owing to the presence of peppermint oil in the oral TU formulation] compared to topical T patients but these were transient, minor in severity and did not result in any patients discontinuing oral TU.

Dose titrations were based on a subject's total T Cavg determined from serial PK sampling over a 24-hour period to ensure a the most accurate characterization of a patient's T concentration.[27] However, dose titrations based on 24-hour sampling are not practical in clinical medicine and thus PK analyses were conducted to demonstrate that a single sample drawn between 4 and 6 hours after the AM oral TU dose could effectively guide dose titration. Total concordance for dose titration between the 4 (C4) and 6 (C6) hour T concentrations after oral TU administration and Cavg was exceptionally strong [C4: 88–93%; C6: 96–98%] at both titration visits. This indicates that dose-titration decisions based on a single status blood sample drawn from men dosed with oral TU can be used to effectively guide dose titration in a real-world clinical setting.

Although efficacy of TRT therapies in the U. S. is based solely on T PK parameters, the clinical benefit is better assessed using patient reported outcomes such as the PDQ questionnaire. This questionnaire assesses the patient's sexual health along several domains. In the Testosterone Trials, question 4 of the PDQ questionnaire was one of the primary endpoints and clinically meaningful score change was determined using data from this study.[2,28] In the present study, there were statistically significant improvements in all domains of the questionnaire in both treatment groups. Of particular note, oral TU was associated with a significant increase (both statistically and from a clinical perspective) in the sexual activity domain—a finding consistent with that observed with topical T in this study and in the T trial in older men.[28]

Oral TU was associated with a small but significant increase in systolic BP versus topical T. The observed increase in systolic BP in some oral TU patients is consistent with effects reported for a new parenteral (subcutaneous) form of T-enanthate now marketed in the U. S.,[29] an older formulation of TU available outside the U. S. [Andriol;[30]] and an oral TU product in phase 3 development [ClinicalTrials.gov identifier: NCT No. 03868059)[31]]. In an effort to determine the etiology of elevated BP we explored the potential relationship between rise in BP to numerous other factors (data not included herein), including: oral TU dose, total and free T, estradiol and DHT concentrations; changes in hematocrit, hemoglobin (as a surrogate for viscosity and increase in plasma volume), potassium (as a surrogate of possible increases in mineralocorticoid levels/activity), and heart rate (as a surrogate of increases in β-adrenergic receptor activity). None of these factors correlated with elevation in systolic BP (R2 < 0.04).

The clinical significance of a 3 to 5 mmHg rise in systolic BP in hypogonadal men who have increased cardiovascular risk[32] as result of long-standing T deficiency is unclear. Meta-analyses of large population-based prospective studies demonstrate elevations in BP are directly related to an increased risk of major adverse cardiovascular events including myocardial infarction, strokes and death.[33] However, in individual patients, clinically important changes in systolic BP (e.g., confirmed increases > 10 mmHg or resultant values which increase to > 140 mmHg) are detectable by clinicians after initiating treatment with T and can be suitably managed. Importantly, guidelines for the management of hypertension are based on absolute values of the BP and hypertension categories rather than changes in BP.[34] During the present study, BP changes in both the oral TU and topical T patients resulted in shifts to higher hypertension categories as evidenced by the fact that the percentage of patients in each treatment group that shifted upwards into Stage 1(130–139/80–89 mmHg) or Stage 2 (≥140/90 mmHg) hypertensive categories was comparable.

Testosterone replacement therapy is known to promote sodium and fluid retention,[35] and this may be at least one mechanism leading to elevated BP in some men dosed with oral TU. Regardless of the etiology, careful BP monitoring should be added to the other routine monitoring of men who are receiving oral TU. In addition, men treated with oral TU who have controlled hypertension should be monitored for potential increases in BP that would warrant changes to their hypertension treatment and potential cessation of oral TU.

In prior studies, we have shown that the ex vivo conversion of TU to T, as manifested by increases in T concentration after sample collection, was observed in blood samples collected from men receiving oral TU. The rate of conversion was more rapid in the blood samples held at room temperature than kept on ice or collected in tubes that did not contain NaF, a non-specific inhibitor of esterase activity.[15] In the present study, T levels used for dose-titration decisions measured in NaF-EDTA plasma to minimize the ex-vivo contribution of TU to T measurements. However, in clinical practice, serum is the preferred matrix for T assays. Therefore, we performed a separate study to derive and validate a conversion factor that could be used to convert NaF-EDTA plasma T concentrations in men dosed with oral TU into approximate equivalent serum T concentrations.

Oral delivery of T is simple, convenient and should foster improved patient adherence—a well-described problem with topical T products.[36] In addition, oral T administration avoids the potentially painful injection of T-esters (including TU) and eliminates all risk of T transference to women and children, the risk associated with topical gel/solution products. Oral TU was not been associated with liver toxicity in the present study nor in prior clinical studies of this oral TU formulation in which men were treated with oral TU as higher dosages dosed for up to 2 years (ClinTrials.gov: NCT01403116 and NCT01699178). Nor has the new oral TU product been observed to have an overall safety profile different from T replacement products as a class—with the possible exception of effects on BP. However, the magnitude of oral TU effect on BP was the same as that observed for a weekly injected (s.c.) T-enanthate formulation when BP was measured by ABPM.[29]

Our study has several strengths and weaknesses. This is the first published study of oral TU in hypogonadal men to demonstrate pharmacokinetic efficacy in line with current U. S. regulatory approval standards. Second, we have demonstrated by two different but related analyses that a single blood sample can be collected about 4–6 hours after the morning oral TU dose to assess the approximate average concentration of T over the dosing interval to reliably guide needed dose adjustments. Third, we have demonstrated that the dose titration scheme prospectively evaluated in this study is robust based on the overall percentage of men who achieved eugonadal T levels and close alignment of peak concentrations with targets established by FDA. Finally, we factored into the study design the potential conversion of TU to T in blood samples collected for T assay in order to generate accurate T measurements on which efficacy was determined. These data, when combined with data from another study (unpublished), enabled us to determine a means by which oral TU response and dose adjustment in a real-world clinical setting can be achieved on the basis of T measured in serum using standard procedures. In contrast to these strengths, studies of this type are not designed to provide outcomes data relative to long-term safety and efficacy parameters and thus, the number of patients evaluated was relatively small. Similarly, the length of oral TU treatment was also fairly brief. Nonetheless, we demonstrated an efficacy and safety profile largely consistent with that observed for a topical T comparator and currently available T replacement products, as a general class.

We conclude that the new oral TU formulation evaluated in this study is a safe and effective means to treat hypogonadal men and has an overall profile consistent with the class of available TRT products but there exists the potential that oral TU may increase systolic BP in some men. The validated dosing and dose adjustment schedule for oral TU should enable treated men to achieve a consistent mean daily T response in the mid-eugonadal range. Oral TU administration is convenient and twice-daily dosing with food (i.e., with breakfast and dinner containing a typical amount of fat) is a simple regimen that may enhance adherence over transdermal and injectable T products that dominate use among hypogonadal men but are associated with pain of administration (injected T-esters) or with transfer of T to women and children.

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