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Trelstar - Scientific Information

Manufacture: Actavis
Country: Canada
Condition: Prostate Cancer
Class: Gonadotropin releasing hormones, Hormones/antineoplastics
Form: Intramuscular (IM), Powder
Ingredients: Triptorelin Pamoate, Poly-d,l-lactide-co-glycolide, Mannitol, Carboxymethylcellulose Sodium And Polysorbate 80

Pharmaceutical information

Drug Substance

Proper Name: Triptorelin pamoate
Chemical Name: 5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L- tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolylglycine amide, pamoate salt
Structural Formula: Upper formula      (D-Trp6)-LHRH
Lower formula      Pamoic acid (embonic acid)
All optically active amino acids are in L-configuration except where marked (*) for D-configuration.
Molecular Formula:
C64H82N18O13•C23H16O6
Molecular Weight:
1699.9
Description: Yellowish powder, specific optical rotation [α]D25 = - 23.0o ± 2.5o
Physicochemical Properties:
Soluble in DMSO (660 mg/mL), pyridine (440 mg/mL) and water (60 μg/mL)

Clinical trials

Clinical Studies with Triptorelin Acetate

Three European, multicenter, long-term controlled studies, involving a total of 265 patients (160 triptorelin acetate, 105 orchiectomy) were conducted to assess the efficacy and safety of a triptorelin acetate 3.75 mg formulation for the treatment of advanced prostate cancer. A pharmacodynamic equivalence study in 24 healthy volunteers showed the equivalence of the triptorelin acetate formulation with the pamoate formulation currently marketed, in the terms of serum testosterone pharmacodynamics.

The primary efficacy criteria in all three studies were the reduction of serum testosterone to castration level (≤ 1.735 nmol/L) and relief of clinical symptoms (bone pain and urinary symptoms). The mean age was 73 years in both the triptorelin and orchiectomy treatment groups. The mean weights were 71 kg and 70 kg in the triptorelin and orchiectomy treatment groups, respectively. Of those evaluated, a similar proportion of patients in each group had Stage C (20% and 21%) or Stage D (80% and 79%) prostate cancer for triptorelin and orchiectomy patients, respectively.

The efficacy results of the studies showed that monthly i.m. administration of triptorelin (3.75 mg) reduced serum testosterone levels in patients with advanced prostate cancer to an extent similar to that achieved after surgical orchiectomy: 73% of the patients in the triptorelin group and 74% of the patients in the orchiectomy group were at the castration level (≤ 1.735 nmol/L) at Month 1; 75% of the patients in the triptorelin group and 80% of the patients in the orchiectomy group were at the castration level (≤1.735 nmol/L) of testosterone at Month 24. The effectiveness of this reduction in testosterone was confirmed by a relief of clinical symptoms which were comparable for triptorelin treatment and orchiectomy.

These studies also showed that triptorelin acetate was well-tolerated. Adverse events reported by 1% or more of patients and considered possibly or probably related to the study drug are listed in Table 1.

TABLE 1. INCIDENCE (%) OF POSSIBLY OR PROBABLY RELATED SYSTEMIC ADVERSE EVENTS REPORTED BY 1% OR MORE OF PATIENTS TREATED WITH TRELSTAR (TRIPTORELIN ACETATE 3.75 MG FORMULATION) AND ORCHIECTOMY
Triptorelin Acetate (3.75 mg)
N = 156
n (%)
Orchiectomy
N = 97
n (%)
Application Site Disorders
Injection site pain

6 (3.8)

NA
Body as a Whole
Hot flushes*
Oedema
Asthenia
Back pain
Fatigue
Pain

70 (44.9)
6 (3.8)
6 (3.8)
3 (1.9)
2 (1.3)
2 (1.3)

42 (43.3)
2 (2.1)
3 (3.1)
0 (0.0)
0 (0.0)
2 (2.1)
Cardiovascular Disorders
Heart disorder
Angina pectoris
Flushing
Hypertension
Hypotension
Palpitation

5 (3.2)
1 (0.6)
0 (0.0)
2 (1.3)
0 (0.0)
1 (0.6)

1 (1.0)
3 (3.1)
2 (2.1)
0 (0.0)
1 (1.0)
1 (1.0)
Gastro-intestinal
Vomiting
Constipation
Diarrhoea
Bad defecation

4 (2.6)
3 (1.9)
3 (1.9)
0 (0.0)

4 (4.1)
1 (1.0)
1 (1.0)
1 (1.0)
Endocrine
Reduced size of genitalia*
Gynecomastia

19 (12.2)
2 (1.3)

NA
0 (0.0)
Metabolic and Nutritional Disorders
Weight increase
Weight decrease
Cachexia

8 (5.1)
2 (1.3)
2 (1.3)

4 (4.1)
2 (2.1)
0 (0.0)
Neoplasms
Tumor flare

4 (2.6)

0 (0.0)
Nervous System
Vertigo

0 (0.0)

1 (1.0)
Psychiatric Disorders
Impotence*
Libido decreased*
Nervousness
Depression*
Anorexia
Aggressive reaction

78 (50.0)
70 (44.9)
4 (2.6)
3 (1.9)
2 (1.3)
0 (0.0)

40 (41.2)
38 (39.2)
1 (1.0)
2 (2.1)
1 (1.0)
1 (1.0)
Respiratory System Disorders
Dyspnoea
Respiratory disorder
Haemoptysis

6 (3.8)
1 (0.6)
0 (0.0)

0 (0.0)
1 (1.0)
1 (1.0)
Resistance Mechanism Disorder
Infection

0 (0.0)

1 (1.0)
Skin and Appendages Disorders
Pruritis
Rash
Sweating increased

2 (1.3)
0 (0.0)
1 (0.6)

0 (0.0)
1 (1.0)
1 (1.0)
Urinary System Disorders
Micturition frequency
Urinary incontinence

3 (1.9)
2 (1.3)

2 (1.3)
1 (1.0)
Unknown**
Unknown

3 (1.9)

0 (0.0)

NA = not applicable; * Expected pharmacological consequence of testosterone suppression; ** Data were insufficiently clear to be coded in three patients

Clinical Studies with Triptorelin Pamoate

TRELSTAR 3.75 mg (1-month, 3.75 mg triptorelin pamoate formulation) and TRELSTAR 11.25 mg (3-month, 11.25 mg triptorelin pamoate formulation)

A study involving 348 patients was conducted to compare TRELSTAR 3.75 mg (173 patients) and TRELSTAR 11.25 mg (175 patients) in subjects with advanced prostate cancer.

The primary objectives of this study were to demonstrate that the 3-month formulation (TRELSTAR 11.25 mg) of triptorelin pamoate is at least as effective as the 1-month formulation (TRELSTAR 3.75 mg) of triptorelin pamoate in terms of the percentage of patients achieving castration levels of serum testosterone (≤1.735 nmol/L) on Day 29 following initial intramuscular injection and the percentage of patients maintaining castration levels of serum testosterone from Months 2 to 9 of treatment.

The mean age of the 346 patients in the safety population was 70.5 years (range: 45 to 96 years). One hundred and sixty-five (165) of these patients were Caucasian, 130 were Black, and 51 were Other. Mean height was 172 cm (range 153 to 195 cm), and mean weight was 72.9 kg (range: 38 to 129 kg). There was no clinically significant difference in age, race, height or weight between the two treatment groups. The mean onset of prostate cancer was 69.8 years (range: 44 to 96 years), and the mean disease duration was 6.9 months (range: 0 – 155 months). All patients, except one in the safety population had histologically proven prostate cancer. One hundred eighty-three of the patients had prostate cancer at stage C and 162 had prostate cancer at stage D.

The efficacy results showed that the 3-month formulation of triptorelin pamoate was able to induce a chemical castration (≤ 1.735 nmol/L) in 162 out of 166 patients (97.6%) 28 days after the first i.m. injection. In the 1-month formulation group, 147 out of 159 (92.5%) patients were chemically castrated (≤ 1.735 nmol/L) 28 days after the first injection. It was concluded that the 3-month formulation (TRELSTAR 11.25 mg) is at least as effective as the 1-month formulation (TRELSTAR 3.75 mg) in achieving castration on Day 29.

TRELSTAR 22.5 mg (6-month, 22.5 mg triptorelin pamoate formulation)

The 6-month formulation, TRELSTAR 22.5 mg, was studied in a non-comparative trial of 120 men with advanced prostate cancer in South Africa. Patients received the 6-month formulation (N = 120) every 168 days for a total of up to 2 doses (maximum treatment period of 337 days). The primary efficacy endpoints were both achievement of castration by Day 29 and maintenance of castration from Day 57 through Day 337. The clinical trial population consisted of 64% Caucasian, 23% Black, and 13% Other. Men were between 51 and 93 years of age (mean = 71 years).

The efficacy results showed that castration levels of serum testosterone (≤ 1.735 nmol/L) were achieved at Day 29 in 117 of 120 (97.5%) patients treated with the 6-month formulation. Maintenance of castration levels of serum testosterone from Day 57 through Day 337 was found in 93.0% of patients treated with the 6-month formulation.

Detailed pharmacology

Triptorelin is a potent agonist of LHRH. The potency relative to native LHRH has been demonstrated both in vitro and in vivo. Comparative in vitro studies showed that triptorelin was 100-fold more active than native LHRH in stimulating LH release from monolayers of dispersed rat pituitary cells in culture and 20-fold more active than native LHRH in displacing 125I-LHRH from pituitary receptor sites. The increased potency was correlated with an increased resistance to degradation on exposure to enzyme preparations derived from rat hypothalamus or anterior pituitary. In vivo studies in immature male rats showed that triptorelin had 13-fold higher LH- releasing activity and 21-fold higher FSH-releasing activity compared to native LHRH. Compared with the ovulating-inducing capacity of native LHRH in adult Sprague-Dawley rats and Swiss albino mice, triptorelin was 84-fold more potent in proestrus rats (pretreated with fluphenazine to block ovulation), 372-fold more potent in pregnant rats, 85-fold more potent in diestrus rats, and 63-fold more potent in diestrus mice.

A series of experiments showed that long-term administration of triptorelin inhibited prostate cancer growth in male rats that had been inoculated subcutaneously with Segaloff 11095 rat prostate tumor, a chemically-induced, androgen-dependent squamous cell carcinoma; in male rats bearing Dunning R3227 rat prostate tumor, a spontaneous androgen-dependent adenocarcinoma with characteristics similar to human prostate adenocarcinoma; in male rats bearing an androgen-independent Dunning R3327_AT_1 prostate tumor; and in male nude mice bearing xenografts of the hormone-dependent human prostatic tumor PC-82.

In both rats and human prostate tumors, two classes of binding sites were found for triptorelin, one with high affinity and low binding capacity and the other with low affinity and high binding capacity. In rats with prostate tumors, chronic treatment with triptorelin produced down- regulation of membrane receptors for LHRH in the tumors. Additionally, direct antiproliferative effects of LHRH agonists were demonstrated in vitro for both androgen-independent Dunning R3327-AT-1 rat prostate cancer cells and androgen-sensitive human LNCaP prostatic cancer cells.

In male rats, chronic administration of triptorelin caused a decrease in weights of testes, seminal vesicles, and prostate; a fall in blood testosterone levels; inhibition of spermatogenesis; and a reduction of testicular LH/hCG and PRL receptors. Experiments in hypophysectomized animals showed that some of these effects result from the direct action of triptorelin on testicular LH receptors. In both adult and immature hypophysectomized male rats, daily injections of 2μg triptorelin for 7 days decreased the number of testicular LH/hCG binding sites. The effects of triptorelin on testicular LH receptors were biphasic and could be nullified by LHRH antagonists. In hypophysectomized adult male rats primed with pregnant mare serum, daily administration of 200 ng triptorelin reduced the number of testicular LH receptors to 60% of control values, but a 1 ng dose increased receptors to 485% of control values. Both effects were nullified when an antagonist was administered concomitantly with triptorelin.

In female rats, chronic administration of triptorelin or other LHRH agonists caused a delay in vaginal opening, reduction in ovarian and uterine weight; interference with implantation and termination of gestation; and a decrease in the number of ovarian receptors for LH/hCG.

Toxicology

Acute Toxicity Studies

In acute toxicity studies, no clinical symptoms were observed in either mice or rats with single doses up to 10 mg/kg triptorelin.

Subchronic and Chronic Toxicity Studies

In subchronic and chronic toxicity studies of triptorelin, triptorelin acetate microspheres, and triptorelin pamoate microgranules in rats, beagle dogs, and monkeys, the only effects observed were expected consequences of the physiologic action of the drug. Serum levels of testosterone (in males), estradiol and progesterone (in females), and LH were suppressed in animals (rats, dogs, monkeys) administered 2μg/kg/day and higher doses of triptorelin by daily injection or administered the equivalent average daily dose by once monthly intramuscular injection of a sustained release formulation (triptorelin acetate microspheres or triptorelin pamoate microgranules). At the same dose levels, spermatogenic arrest and atrophy of the testes and accessory sex organs were observed in male animals (rats, dogs, monkeys) and inhibition of estrus and atrophy of the ovary and accessory sex organs were observed in female animals (rats, dogs, monkeys). In both males and females, triptorelin caused decreases in weights of reproductive organs. Changes in the anterior pituitary (focal hyperplasia and benign microadenoma) were detected in male rats administered once monthly injections of triptorelin acetate microspheres or daily injection of triptorelin peptide for 6 months; these changes are commonly observed in rats in response to an altered hormonal environment. No changes were observed in the pituitary in dogs or monkeys after 6 months of drug administration.

On withdrawal of the drug, changes in serum hormones, reproductive organ weights, and microscopic atrophic changes in the gonads and accessory sex organs were reversible. Pituitary hyperplasia and benign microadenoma were not reversible.

Carcinogenicity Studies

Carcinogenicity studies of triptorelin were performed in mice and rats. No oncogenic effects were observed in mice given from 120 to 6000 μg/kg triptorelin pamoate microgranules every 28 days for 18 months. An oncogenic effect in the pituitary gland (adenoma of the pars distalis) which resulted in premature deaths was observed in rats given from 120 to 3000 μg/kg triptorelin pamoate depot formulation every 28 days for 23 months. Changes in the anterior pituitary (focal hyperplasia and microadenoma) were judged to be related to the intrinsic pharmacologic activity of the drug. Similar changes in the anterior pituitary of male rats given triptorelin over a 6 month period had been observed in a chronic toxicity study in male rats.

Reproduction Studies

Developmental toxicity studies of triptorelin were performed in mice and rats. No maternal toxicity, fetal toxicity, or embryotoxic or teratogenic effects were observed when pregnant female mice were given daily subcutaneous injections of 2 to 200μg/kg triptorelin on days 6 through 15 of gestation. No maternal toxicity, fetal toxicity, or embryogenic or teratogenic effects were observed when pregnant female rats were given daily subcutaneous injections of 10μg/kg triptorelin on days 6 through 15 of gestation. However, maternal toxicity, demonstrated by reduced weight gain during the treatment period, and an embryotoxic effect, demonstrated by an increase in uterine resorption, were observed when pregnant female rats were given daily subcutaneous injections of 100μg/kg triptorelin on days 6 through 15 of gestation.

Impairment of Fertility

After about 6 months of treatment with triptorelin, atrophy of the genital organs, consistent with reduced fertility, was observed in rats and monkeys at doses ranging from 2 to 2,100μg/kg. These changes were considered to be a reflection of the suppressed gonadal function caused by the pharmacologic activity of the drug. These effects were largely reversed during a 2 or 4 month recovery period. Testicular changes have also been reported after prolonged administration of triptorelin in patients with prostate cancer.

Mutagenicity Studies

The mutagenicity of triptorelin was assessed in vitro and in vivo. Triptorelin showed no mutagenic or clastogenic activity against Salmonella strains, Chinese Hamster Ovary (CHO) cells, and mouse lymphoma cells, under either metabolic activation or non-activation conditions. In the in vivo mouse micronucleus assay, triptorelin -treated animals showed no significant increase in micronucleus frequency compared to negative control, whereas the known clastogenic agent cyclophosphamide induced large and statistically significant increases in micronucleus frequency.