New Oral Testosterone Undecanoate Formulation Restores Normal Testosterone Levels

A new oral testosterone undecanoate formulation can restore testosterone concentrations to normal in hypogonadal men, researchers report.

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"Effective as other testosterone medications, this is a novel oral twice-a-day medication free of hepatic side effects," Dr. Ronald S. Swerdloff of the Lundquist Institute and Harbor-UCLA Medical Center, in Torrance, California, told Reuters Health by email.

The formulation was approved by the U.S. Food and Drug Administration (FDA) in March 2019 and became available in the U.S. in February 2020. It consists of testosterone undecanoate (TU) dissolved in a combination of lipids and other solubilizers and a hydrophilic surfactant which facilitates absorption after oral ingestion and systemic delivery almost exclusively via the intestinal lymphatic system, thereby bypassing the liver. In the circulation, testosterone is liberated from TU via the action of endogenous nonspecific esterases.

Dr. Swerdloff and colleagues assessed the efficacy and safety of this new oral TU formulation versus topical testosterone in a phase-3, open-label clinical trial of 221 clinically hypogonadal men.

At the final pharmacokinetics visit of the study, 87.3% (95% confidence interval, 81.3% to 92.0%) of patients (145/166) in the TU group had an average testosterone value in the eugonadal range, as did 87.3% (95% CI, 75.5% to 94.7%) of patients (48/55) in the topical-testosterone group, the researchers report in The Journal of Clinical Endocrinology and Metabolism.

Maximum serum testosterone levels remained at 1,500 ng/dL or lower in 90.7% of the oral TU group and 97.9% of the topical testosterone group (thereby exceeding the FDA target of 85% or more). Only about 2% had serum testosterone maximum levels >1,800-2,500 ng/dL (below the FDA target of 5% or less), whereas three patients in the TU group and none in the topical testosterone group had levels above 2,500 ng/dL (the FDA target is 0).

Meal types did not significantly affect the pharmacokinetics of the TU formulation in these patients.

Treatment-emergent adverse events deemed related to study drug occurred in 18.7% of patients in the TU group and in 14.5% of the topical testosterone group. Less than 2% of patients in each treatment group prematurely discontinued from the study due to adverse events.

There were no clinically significant changes in the liver function tests in either treatment group.

"While there was a small increase in blood pressure, the clinical significance is uncertain and not likely to be detected except by continuous ambulatory BP monitoring equipment," Dr. Swerdloff said. "This small increase in BP was seen with a subcutaneous injectable testosterone product recently developed and may be a class effect that has not been appreciated."

To monitor testosterone levels in patients receiving oral TU using standard blood-collection techniques, it was necessary to derive a factor that accounted for conversion of TU to testosterone in serum from blood that had clotted at room temperature versus NaF-EDTA blood collection tubes held on ice that prevented this conversion. Applying this conversion factor (1.214) resulted in a mean error of only 3.1%, which the authors say is too small to affect dose-titration decisions.

"An effective oral testosterone medication without hepatic toxicity has been needed for some time," Dr. Swerdloff said. "Finally, my patients with clinically significant low testosterone levels have an oral testosterone-replacement option that will treat their symptoms and restore circulating testosterone levels to the middle range of normal."

He added, "My understanding is that the oral TU formulation we studied will be priced in the same ballpark as other branded testosterone preparations which, of course, will be more expensive than generic topical or injection products. This said, I believe Clarus Therapeutics (the company who developed and is currently marketing the product we evaluated) has an assistance program in place for insured patients that will keep out-of-pocket costs at a level close to their current cost for testosterone therapy."

Dr. Robert Carrasquillo of the University of Miami Miller School of Medicine, in Florida, who recently reviewed new therapies for male hypogonadism, told Reuters Health by email, "The availability of an oral testosterone option can be a game-changer in the world of andrology, as it will likely improve medication compliance due to the ease of administration. Mainstays of testosterone therapy, such as injections, topical gels, and subcutaneous implants, carry risks of injection site pain, skin irritation, topical transference to women or children, and implant-related bleeding, infection, or extrusion."

"It is important to note that oral TU has FDA approval for use in men with hypogonadism due to an underlying medical condition and is not approved for treatment of age-related hypogonadism," he said.

"While semen parameters were not assessed in this trial, levels of LH and FSH were suppressed by use of oral TU," said Dr. Carrasquillo, who was not involved in the study. "Like all testosterone preparations, with perhaps the exception of testosterone nasal gel, oral TU should not be used in men desiring fertility."

Dr. Syed Faisal Ahmed of the School of Medicine at the University of Glasgow, U.K., who recently reviewed testosterone therapy in adolescent boys with hypogonadism, told Reuters Health by email, "There are topical and intramuscular forms, but these may not suit everybody. In Europe we have had another preparation of oral testosterone undecanoate (Restandol) but there are always difficulties in securing a supply of this drug and its (pharmacokinetics) profile has been less reproducible as the authors suggest."

"The fact that you only need to take (the new formulation) twice a day is also good," he said. "Given that in many cases the dose needs to be increased means that the drug could also be used for inducing puberty in adolescents with hypogonadism."

Clarus Therapeutics Inc. supported this study, employed two of the authors and had various relationships with several others.

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