Aveed - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Aveed - Scientific Information

Manufacture: Endo Pharmaceuticals Inc.
Country: United States
Condition: Hypogonadism, Male
Class: Androgens and anabolic steroids
Form: Liquid solution, Intramuscular (IM)
Ingredients: Testosterone undecanoate, benzyl benzoate, refined castor oil.

Description

Aveed (testosterone undecanoate) injection contains testosterone undecanoate (17β-undecanoyloxy-4-androsten-3-one) which is an ester of the androgen, testosterone. Testosterone is formed by cleavage of the ester side chain of testosterone undecanoate.

Testosterone undecanoate is a white to off-white crystalline substance. The empirical formula of testosterone undecanoate is C30H48O3 and a molecular weight of 456.7. The structural formula is:

Figure 1: Testosterone Undecanoate

Aveed is a clear, yellowish, sterile oily solution containing testosterone undecanoate, a testosterone ester, for intramuscular injection.

Each single use vial contains 3 mL of 250 mg/mL testosterone undecanoate solution in a mixture of 1500 mg of benzyl benzoate and 885 mg of refined castor oil.

Clinical Pharmacology

Mechanism of Action

Endogenous androgens, including testosterone and dihydrotestosterone (DHT) are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution.

Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

Pharmacokinetics

Absorption

Aveed 750 mg delivers physiologic amounts of testosterone, producing circulation testosterone concentrations that approximate normal concentrations (300-1000 ng/dL) seen in healthy men.

Testosterone esters in oil injected intramuscularly are absorbed from the lipid phase. Cleavage of the undecanoic acid side chain of Aveed by tissue esterases releases testosterone.

Following intramuscular injection of 750 mg of Aveed, serum testosterone concentrations reach a maximum after a median of 7 days (range 4 – 42 days) then slowly decline (Figure 2). Steady state serum testosterone concentration was achieved with the 3rd injection of Aveed at 14 weeks.

Figure 2 shows the mean serum total testosterone concentration-time profile during the 3rd injection interval (at steady state, 14-24 weeks) for hypogonadal men (less than 300 ng/dL) given 750 mg Aveed at initiation, at 4 weeks, and every 10 weeks thereafter. Intramuscular injection of 750 mg of Aveed generates mean steady state serum total testosterone concentrations in the normal range for 10 weeks.

Figure 2: Mean (SD) Serum Total Testosterone
Concentrations (ng/dL) at 14-24 Weeks

Distribution

Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin.

Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free), and the rest is loosely bound to albumin and other proteins.

Metabolism

Testosterone undecanoate is metabolized to testosterone via ester cleavage of the undecanoate group. The mean (SD) maximum concentration of testosterone undecanoate was 90.9 (68.8) ng/dL on Day 4 following injection of Aveed. Testosterone undecanoate was nearly undetectable 42 days following injection of Aveed.

Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and DHT.

DHT concentrations increased in parallel with testosterone concentrations during Aveed treatment. Average DHT concentrations during a dosing interval ranged from 244 to 451 ng/dL. The mean DHT:T ratios ranged from 0.05 to 0.07.

Excretion

There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. About 90% of a testosterone dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of testosterone or as metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

Effect of Body Weight and Body Mass Index (BMI)

Analysis of serum testosterone concentrations from 117 hypogonadal men in the 84-week clinical study of Aveed indicated that serum testosterone concentrations achieved were inversely correlated with the patient’s body weight. In 60 patients with pretreatment body weight of ≥100 kg, the mean (±SD) serum testosterone average concentration was 426 ± 104 ng/dL. A higher serum testosterone average concentration (568 ± 139 ng/dL) was observed in 57 patients weighing 65 to 100 kg. A similar trend was also observed for maximum serum testosterone concentrations.

In 70 patients with pretreatment body mass index of >30 kg/m2, the mean (±SD) serum testosterone average concentration was 445 ± 116 ng/dL. Higher serum testosterone average concentrations (579 ± 101 ng/dL and 567± 155ng/dL) were observed in patients with BMIs <26 kg/m2 and 26 to 30 kg/m2, respectively. A similar trend was also observed for maximum serum testosterone concentrations.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervicaluterine tumors, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Mutagenicity

Mutagenic effects of testosterone undecanoate were not detected in a battery of in vitro tests including bacterial mutation assays (Ames test) and chromosomal aberration tests in human lymphocytes. Testosterone undecanoate was also negative in an in vivo bone marrow micronucleus assay in mice. Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.

Impairment of Fertility

The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

Clinical Studies

Testosterone Replacement Therapy

Aveed was evaluated for efficacy in an 84-week, single-arm, open-label, multicenter study of 130 hypogonadal men. Eligible patients weighed at least 65 kg, were 18 years of age and older (mean age 54.2 years), and had a morning serum total testosterone concentration <300 ng/dL (mean screening testosterone concentration 215 ng/dL). Patients were Caucasian (74.6%), Black (12.3%), Hispanic (10.8%) and of Other ethnicities (2.3%). The mean body mass index was 32 kg/m2.

All patients received injections of Aveed 750 mg at baseline, at 4 weeks, and then every 10 weeks thereafter.

The primary endpoint was the percentage of patients with average serum total testosterone concentration (Cavg) within the normal range (300-1000 ng/dL) after the third injection, at steady state.

The secondary endpoint was the percentage of patients with maximum total testosterone concentration (Cmax) above three predetermined limits: greater than 1500 ng/dL, between 1800 and 2499 ng/dL, and greater than 2500 ng/dL.

A total of 117 out of 130 hypogonadal men completed study procedures through Week 24 and were included in the evaluation of testosterone pharmacokinetics after the third Aveed injection. Ninety-four percent (94%) of patients maintained a Cavg within the normal range (300 to 1000 ng/dL). The percentages of patients with Cavg below the normal range (less than 300 ng/dL) and above the normal range (greater than 1000 ng/dL) were 5.1% and 0.9%, respectively.

Table 1 summarizes the mean (SD) serum total testosterone pharmacokinetic parameters at steady state for these 117 patients.

Table 1: Mean (SD) Serum Total Testosterone Concentrations at Steady State
Aveed 750 mg
(N=117)
Cavg (0 to 10 weeks) (ng/dL) 495 (142)
Cmax (ng/dL) 891 (345)
Cmin (ng/dL) 324 (99)

Cavg = average concentration; Cmax = maximum concentration; Cmin = minimum concentration

The percentage of patients with Cmax >1500 ng/dL was 7.7%. No patient had a Cmax >1800 ng/dL.