Trelstar 3.75 mg - Scientific Information
|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|
|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|
|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)|
Study Demographics and Trial Design
In a randomized, single-blind, clinical trial conducted in 137 women with clinically verified endometriosis comparing triptorelin (3.75 mg IM q4w x 6) with leuprolide (3.75 mg IM q4w x6), triptorelin was shown to be comparable to leuprolide in relieving or reducing the clinical symptoms associated with endometriosis.
Fifty-five (55, 82%) patients in the triptorelin group and 57 (81%) in the leuprolide group completed the six-month treatment phase of the study. The clinical trial population consisted of 97.0% Caucasian and 3.0% Asian in the triptorelin treatment group, and 97.1% Caucasian, 1.4% Asian, and 1.4% Afro-Caribbean in the leuprolide treatment group. The mean patient age was 32 years in both treatment groups. The mean duration of endometriosis was the same (1.2 years, range 0-11) in both groups, and a similar percentage of patients in both groups had minimal, mild, and moderate disease at pre-treatment laparoscopy.
The primary objective of the study was to demonstrate the equivalence of triptorelin and leuprolide, both as 1-month formulations, in terms of reduction in the pelvic pain associated with endometriosis. Reduction of pelvic pain was based on end-of-treatment versus baseline physician ratios for pelvic pain severity (six categories ranging from 0=absent to 5=excruciating). Other efficacy evaluations included endocrine blood levels (FSH, LH, E2), breakthrough bleeding assessment, and pelvic examinations. Safety evaluations included collection of adverse events, hematology and blood chemistry laboratory testing, and bone mineral density testing in a subset of the population (approximately 60 patients).
Of the women who participated in the study, 80% showed reduction in pelvic pain, 100% showed reduction in dysmenorrhea, and 66% showed reduction in dyspareunia from baseline after 6 months of triptorelin therapy. Serum estradiol levels were suppressed (<184 pmol/L) by 4 weeks, and were maintained at suppressed levels for the remainder of the 6 month treatment period. The range of estradiol levels attained at 6 months (24 weeks) of therapy was 17 – 128 pmol/L. By 12 weeks, most women (90%) also became amenorrheic in response to the low levels of estrogen. Once treatment ended, the mean time to return to menses was 81 days (range: 6 – 116). Estrogen levels returned to baseline values by 3 months post treatment.
As shown in Table 1, over 40% of patients in each treatment group were completely free of pelvic pain, over 95% in each group were completely free of dysmenorrhea, and over 80% in each group were free of dyspareunia after 6 months of therapy. After 12 months of follow-up similar percentages of women in each treatment were still free of the pain symptoms associated with endometriosis.
|Pain Symptom||Triptorelin (n=66)
3.75 mg IM q4w x6
3.75 mg IM q4w x6
|6 months of therapy||12 months follow-up||6 months of therapy||12 months follow-up|
|Pelvic Pain||42% (23/55)1||27% (9/33)||46% (27/59)||27% (9/33)|
|Dysmenorrhea||96% (53/55)||16% (5/32)||98% (58/59)||22% (7/32)|
|Dyspareunia||82% (45/55)||70% (23/33)||81% (48/59)||64% (21/33)|
1 Numbers in parenthesis reflect the proportion of patients without pain symptoms over the total number of patients still in the study at that assessment visit.
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 2 μg 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.
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 2 μg/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 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.
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 200 μg/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 10 μg/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 100 μg/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 2,100 μg/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.
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.