sterone undecanoate occurs after the ester bond linking thetestosterone to the undecanoic acid is cleaved by endogenous non-specific esterases.
Undecanoic acid is metabolized like all fatty acids via the beta-oxidation pathway.
Testosterone is metabolized to various 17-keto steroids through two different pathways. Themajor active metabolites of testosterone are dihydrotestosterone (DHT) and estradiol.
Excretion
0
100
200
300
400
500
600
700
800
900
1000
0 2 4 6 8 10 12 14 16 18 20 22 24
Plasma T Concentration (ng/dL)
Time after morning the JATENZO dose (hours)
Normal Range
Final Visit
16
About 90% of a dose of testosterone givene given intramuscularly is excreted in the urine as glucuronicand sulfuric acid conjugates of testosterone and its metabolites. About 6% of a dose is excretedin the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in theliver.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Testosterone has been tested by subcutaneous injection and implantation in mice and rats. Inmice, the implant induced cervical-uterine tumors, which metastasized in some cases.
There issuggestive evidence that injection of testosterone into some strains of female mice increases theirsusceptibility to hepatoma. Testosterone is also known to increase the number of tumors anddecrease the degree of differentiation of chemically induced carcinomas of the liver in rats.
Mutagenesis
Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.
Impairment of Fertility
The administration of exogenous testosterone suppresses spermatogenesis in the rat, dog andnon-human primates, which was reversible on cessation of the treatment.
13.2 Animal Toxicology and/or Pharmacology
JATENZO has been eva luated in 3- and 9-month repeat-dose oral toxicity studies in maleeugonadal dogs. JATENZO caused exaggerated pharmacological effects on androgenresponsivetissues including testes, epididymis, prostate and adrenals at exposures to testosteroneor testosterone undecanoate, comparable to the maximum human exposure based on AUCcomparisons. Following a 4-week drug-free period, a reduced severity of these findings wasobserved, suggesting partial reversibility.
In adrenal glands, moderate to severe atrophy, characterized as thinning of the zona fasciculata,was observed with reduced adrenal weights and reduced circulating levels of cortisol intestosterone undecanoate-treated dogs after 3 months of treatment. Following 9-monthtreatment, there were dose-related decreases in adrenal weights in testosterone undecanoatetreatedmale dogs and moderate adrenal vacuolation in one testosterone undecanoate-treatedmale dog. The clinical significance of these adrenal and cortisol findings is unknown.
14 CLINICAL STUDIES
14.1 Clinical Trials in Hypogonadal Males
The efficacy and safety of JATENZO was eva luated in 166 adult hypogonadal males in an openlabelstudy of approximately 4 months duration (NCT02722278). The studyincluded aScreening Phase, a Treatment Titration Phase, and a Treatment Maintenance Phase.
JATENZO was taken orally at a starting dose of 237 mg twice per day with meals. The dose wasadjusted on Days 21 and 56 between a minimum of 158 mg twice per day and a maximum of 396 mg twice per day on the basis of the average testoster |
