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

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Amenorrhea, Endometriosis, Prostate Cancer, Uterine Fibroids
Class: Gonadotropin releasing hormones, Hormones/antineoplastics
Form: Liquid solution, Subcutaneous (SC)
Ingredients: Triptorelin acetate, are sodium chloride, acetic acid (glacial), water for injection.

Pharmaceutical Information

Drug Substance

Proper name: Triptorelin Acetate
Chemical name: 5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-Dtryptophyl-L-leucyl-L-arginyl-L-prolylglycinamide, acetate salt
Abbreviated chemical name: Pry-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2, acetate salt
Molecular formula and molecular mass:
Molecular Formula: C64H82N18O13 (net)
C644H82N18O13 C2H4O2 (Triptorelin Acetate)
Molecular Mass: 1311.5 (net) + 60.1 (acetate) = 1371.6 (Triptorelin Acetate)
Structural formula:


Physicochemical properties: Freely soluble in acetic acid; soluble in water, 0.1 M hydrochloric acid, 0.1 M sodium hydroxide, DMF; practically insoluble in acetone and chloroform.

Clinical Trials

Study Demographics and Trial Design

Table 1- Summary of patient demographics for clinical trials in specific indication
Study # Trial design Dosage, route of
administration and
duration
Study
subjects
(n=number)
Mean
age
(Range)
Primary
Endpoint
MFK/IVF/0 399E (ART) Randomised (HPhMG versus FSH) , open

Stimulation with HP-hMG or rFSH, then individual adjustment

Fixed dose of 225 IU HP Menotrophin for 5 days. Investigator adjusted until criteria was met or patient withdrawn for poor response; for a maximum of 20 days.
Decapeptyl 0.1 mg SC

Decapeptyl Depot 3.75 mg (single injection)

Other GnRH agonists
GnRH agonist: 781, COH: 727

Decapeptyl 0.1 mg SC: 117 started down regulation, 113 started down regulation with Decapeptyl 0.1 mg and underwent COH
18-38 years Ongoing pregnancy rate
FE999906 CS003 (ART) Randomized (HP - hMG versus rFSH) open, assessor blind

Stimulation with HP-hMG or rFSH (225 IU for first 5 days, then individual adjustment)
Decapeptyl 0.1 mg SC Decapeptyl 0.1 mg SC: 781
Randomised to HP-hMG or rFSH for COH: 731
21-37 years Ongoing pregnancy rate

Study Results

MFK/IVF/0399E and FE999906 CS003 were large randomised, multi-centre studies comparing MENOPUR and recombinant FSH in patients (18-38 years) undergoing controlled ovarian hyperstimulation for IVF/ICIS following the long GnRH agonist protocol starting in the mid-luteal phase. In MFK/IVF/0399, several GnRH agonists were used for downregulation. A total of 781 patients started downregulation, of whom 117 were given DECAPEPTYL 0.1 mg. Adequate downregulation was established by serum estradiol < 200 pmol/l (56 pg/mL) and no ovarian cysts. In FE999906 CS003 patients (21-37 years) diagnosed with tubal or unexplained infertility, including endometriosis stage III/IV and mild male factor eligible for IVF were enrolled. In this study, 781 patients started downregulation and all received DECAPEPTYL 0.1 mg SC daily. Confirmation of downregulation prior to randomisation to menotropin or recombinant FSH was defined as menstrual bleeding and transvaginal untrasound showing a shedded endometrium with a thickness of < 5 mm and no ovarian cysts or serum E2 50 pg/mL and no ovarian cysts. A total of 898 patients were exposed to DECAPEPTYL 0.1 mg SC in these two studies. The primary endpoint in MFK/IVF/0399E and FE999906 CS003 was ongoing pregnancy rates (defined as at least one viable fetus at 10-11 weeks after embryo transfer) after one cycle. In FE99906 CS003, a strict protocol and treatment approach were implemented to minimize sources of variation in the study, including harmonisation of concomitant fertility treatments, a pre-specified stimulation goal and homogeneity of other major pre-and post-randomisation interventions.

A post-hoc evaluation of treatment outcome according to duration of downregulation was performed in FE999906 CS003. The ongoing pregnancy rate by duration of treatment with DECAPTEPTYL 0.1 mg before the start of ovarian stimulation is tabulated in the table below:

Ongoing pregnancy rate by duration of DECAPEPTYL 0.1 mg SC treatment before start of ovarian stimulation (FE999906 CS003)
Duration of DECAPEPTYL 0.1 mg alone
< 14 days 14-20 days ≥ 21 days
Ongoing pregnancy rate 56/270 (21%) 100/385 (26%) 23/76 (30%)

In FE999906 CS003, the ongoing pregnancy rate increased with increasing duration of treatment with DECAPEPTYL 0.1 mg prior to gonadotropin administration. The ongoing pregnancy rates were 21%, 26% and 30% among patients who had taken DECAPEPTYL alone for < 14 days, 14-20 days and ≥ 21 days respectively. The data suggests that longer duration of pituitary downregulation prior to start of stimulation positively influences ongoing pregnancy rate.

The treatment outcome associated with different types of GnRH agonists can be derived from MFK/IVF00399E. Comparative data with respect to ongoing pregnancy rate are shown below:

Ongoing pregnancy rate by GnRH Agonist (MFK/IVF/0399E)
DECAPEPTYL 0.1 mg All other GnRH agonists1
Ongoing pregnancy rate 24% (27/113) 22% (133/614)

1 DECAPEPTYL depot 3.75 mg, buserelin, leuprolide, goserelin, nafarelin

Among the 113 patients who were downregulated with DECAPEPTYL 0.1 mg, the ongoing pregnancy rate was 24% (27/113). Although this study was not designed for this investigation, the findings suggest that the ongoing pregnancy rate associated with DECAPEPTYL 0.1 mg SC daily is not different from that observed with other GnRH agonists.

Ongoing pregnancy rate by GnRH Agonist (MFK/IVF/0399E)
DECAPEPTYL
0.1 mg
DECAPEPTYL Depot
3.75 mg
Other GnRH
agonists1
Ongoing pregnancy rate 24% (27/113) 21% (96/466) 25% (37/148)

1 buserelin, leuprolide, goserelin, nafarelin

The ongoing rate was 21% for patient’s downregulated with DECAPEPTYL Depot 3.75 mg, and 25% for those who had used other GnRH agonists (daily or depot). The data showed that DECAPEPTYL 0.1 mg is at least as efficacious as other available GnRH.

Detailed Pharmacology

Mechanism of Action

Triptorelin is a GnRH analogue with increased receptor-binding abilities as compared to GnRH and with longer plasma half-life. Treatment with triptorelin lowers the plasma concentration of luteinizing hormone in a reversible manner

Pharmacodynamics

The superagonistic effects of triptorelin on the luteinizing hormone-release hormone receptor in the anterior pituitary was demonstrated in studies in vitro and in vivo. In vitro studies demonstrated that triptorelin displaces GnRH from the GnRH receptors and in vivo treatment with triptorelin resulted in a decrease in plasma concentrations of luteinizing hormone and follicle stimulating hormone in rats, dogs and baboon monkeys. When triptorelin treatment was terminated the blood hormone levels returned to normal.

Pharmacokinetics

There were no differences between the pharmacokinetics of triptorelin in rats, dogs and humans. Following subcutaneous administration the maximum plasma concentration of triptorelin was reached within a few hours and as the half-life of triptorelin was short, there was no accumulation of triptorelin following daily administration. The human half-life corresponded to that of animals (3-5 hours versus 2 hours in dogs and < 6 hours in rats). Results from the dog studies indicate that the subcutaneous bioavailability was approximately 100%.

The dose-adjusted values of Cmax and AUC when administering triptorelin subcutaneously are comparable between dogs and humans.

Once- a-month intramuscular administration of microparticles containing triptorelin resulted in an initial surge in plasma concentration of triptorelin followed by declining plasma concentration during the following 30 days. Triptorelin was present in both rats and dogs 30 days after treatment indicating that the animals had been continuously exposed during that period. Data from toxicokinetics studies in dogs and a clinical study in patients established the bioavailability of triptorelin to be approximately 40% when administered intramuscularly as the depot formulation.

Toxicology

Single Dose Toxicity Studies

Single dose intraperitoneal toxicity studies using up to 200,000 μg triptorelin/kg b. wt. were performed in mice and rats. The No-Observed-Adverse-Effect-Level (NOAEL) of triptorelin was 100,000-160,000 μg/kg b. wt. in mice and 10,000 μg/kg b. wt. in rats. The lowest lethal doses were 200,000 μg/kg b. wt. for male mice (not established for females) and 100,000 μg/kg b. wt. for rats. The maximum human therapeutic dose of 100 μg/day corresponds to an approximate dose level of 1.4 μg/kg b. wt. in a 70 kg person. This corresponds to 7,000 times the NOAEL in rats and 70,000 times the NOAEL in mice. Triptorelin can thus be considered to have a very low acute toxicity with respect to its therapeutic dose.

Single Dose Toxicity Studies
Species Route of
Administration
No-Observed-Adverse-
Effect-Level
Lowest Lethal Dose
Mice i.p. Male: 160,000 μg/kg
Female: 100,000 μg/kg
Male: 200,000 μg/kg
Female: Not established
Rats i.p. Male: 10,000 μg/kg
Female: 10,000 μg/kg
Male: 100,000 μg/kg
Female: 100,000 μg/kg

Repeat-Dose Toxicity Studies

Repeat-dose toxicity studies were performed in rats, dogs and monkeys. In an intramuscular 45-day study in rats the NOAEL was found to be 609 μg/kg b. wt./day. In the 26-week studies, the NOAEL for rats and monkeys treated subcutaneously was 200 μg/kg b. wt./day and 20 μg/kg b. wt./day for dogs treated intramuscularly.

Repeat-dose toxicity studies
Species Route of Treatment,
Duration of Study
NOAEL
(μg/kg b. wt./day
Rats i.m., 45 days 609
Rats s.c., 26 weeks 200
Dogs i.m., 26 weeks 20
Monkeys s.c., 26 weeks 200

A maximum human therapeutic dose of 100 μg/day approximates a dosage of 1.4 μg/kg b. wt./day, is 143 times lower than the NOAEL in rats and monkeys (200 μg/kg b. wt./day). In dogs, the ratio between the NOAEL and the human therapeutic dose is 14. Women receiving triptorelin therapy for IVF are likely to be exposed for approximately 28 days. In the 26-week dog study the high dosage animals received a total of 3640 μg/kg which is 90 times more than the expected total human dosage.

Gentoxicity

Three in vitro gentoxicity studies were performed: One mutagenicity test with the bacterium Salmonella typhimurium, a test with mouse lymphoma L5178Y cells, and a test with Chinese hamster ovary cells. A micronucleus test in vivo was performed in mice. There were no evidence of mutagenic or clastogenic potential of triptorelin in concentrations up to 5000 μg/plate or 5000 μg/mL in the studies in vitro and 160,000 μg/kg b. wt. in the study in vivo.

Carcinogenicity

Monthly intramuscular treatment of rats with microparticles containing triptorelin at dose levels up to 6,000 μg/kg b. wt./month (214 μg/kg/b. wt) had no carcinogenic effect in mice. In the rat study, dosage of 120, 600 and 3,000 μg/kg b. wt. /month (107μg/kg/b.wt.), triptorelin resulted in a dose-related mortality in rats and dose-related proliferative lesions (adenomas) in the pituitary only. No signs of mutagenicity or clastogenicity were recorded in the genotoxicity tests, triptorelin is considered unlikely to be carcinogenic in humans.

Reproductive Toxicity Studies

Studies on reproductive toxicity were performed in rats, rabbits and monkeys.
Treatment disrupted the female cycles, but after recovery there were no treatment related findings on fertility. No embryotoxic or teratogenic effects were seen.

Non-pregnant rats were treated for 60 days by subcutanous administration of triptorelin at dose levels up to 200 μg/kg./day by daily subcutaneous injections. There was a treatment related delay in the recovery of female cycles once treatment was terminated, but after recovery and subsequent mating there were no effects on fertility or reproductive performance. Further, there were neither embryotoxic or teratotoxic effects nor effects on late prenatal and postnatal offspring development.

Pregnant rats were treated by subcutaneous administration of triptorelin at dose levels of 0.4, 2 or 10 μg/kg/day during the period of organogenesis No signs of maternal toxicity or teratogenicity were seen. However, a substantial increase in the number of luteal bodies was seen in all treated groups. Treatment with 2 μg/kg caused a slight increase in the mean placental weight while treatment with 10 μg/kg caused a marked increase in placental weight.

Pregnant rabbits were treated by subcutaneous administration of triptorelin to at dose levels of 0.5, 5 or 50 μg/kg/day during the period of organogenesis. Pre-implantation losses were observed in rabbits treated with the highest dose. When compared with the control group, a higher incidence of resorptions and abortions were observed at 50.0 µg/kg/day dosage. Fetal survival, growth and morphological development were unaffected at dose-levels up to 50.0 µg/kg/day.

Pregnant Cynomolgus monkeys were given single intramuscular injections of 1500 μg triptorelin/animal (ca. 375 μg/kg) as a slow release formulation on day 10 and day 40 post-coitum The treatment did not affect parturition and had no maternal or embryotoxic effects.

Local Toxicity Studies

There are no studies on the local toxicity of DECAPEPTYL. However, several studies on local toxicity were performed in rabbits using triptorelin microparticles. No signs of systemic toxicity were seen in these studies and the subcutaneous treatment with triptorelin microparticles caused only transient local reactions (edema, erythema).