Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2022 Publisher: Ipsen Pty Ltd, Level 2, Building 4, Brandon Office Park, 540 Springvale Road, Glen Waverley Victoria 3150 Telephone: 1800 317 033
Pharmacotherapeutic group: Hormones and related agents, gonadotropin releasing hormone analogues
ATC code: L02AE04
Triptorelin, a gonadotrophin releasing hormone (GnRH) agonist, inhibits gonadotrophin secretion when given continuously and in therapeutic doses. Male animal and human studies show that after the administration of triptorelin there is an initial and transient increase in circulating levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone. However, chronic and continuous administration of triptorelin results in decreased LH and FSH secretion and suppression of testicular and ovarian steroidogenesis. A reduction of serum testosterone levels into the range normally seen in surgically castrated men occurs approximately 2 to 4 weeks after initiation of therapy. This results in accessory sexual organ atrophy. These effects are generally reversible upon discontinuation of the medicinal product.
In animals, administration of triptorelin resulted in the inhibition of growth of some hormone-sensitive prostate tumours in experimental models.
One pivotal, long-term (9 months), controlled, Phase III, multicentre study (DEB-96-TRI-01, first phase) compared the 3.75mg (1 month) and 11.25mg (3 month) embonate formulations in 348 patients with advanced prostatic cancer. Patients in this study had histologically confirmed stage C (52.9% of patients) or D (46.8% of patients) prostate cancer with testosterone levels greater than 5nmol/L at baseline. The mean age of the 348 patients in the safety population was 70.5 years (range 45 to 96 years); mean age at onset of prostate cancer was 69.8 years (range 44 to 96 years) and the mean disease duration was 6.9 months (range 0 to 155 months).
Per protocol and intent-to-treat analyses produced similar results. The 3-month formulation was non-inferior (no worse than 10 percentage point difference in incidence) to the 1-month formulation in inducing and maintaining chemical castration (Table 3).
Table 3. Chemical Castration in Advanced Prostate CancerTrial DEB-96-TRI-01 Phase 1 per protocol population:
| Parameter | Triptorelin 11.25 mg q 12w (n=166) | Triptorelin 3.75 mg q 4w (n=159) | Difference [95% CI]4 |
|---|---|---|---|
| Induction by day 291,2 | 97.6% | 92.5% | 5.1% [-1.1%, 13.8%] |
| Maintenance 2-9 mths3 | 94.1% | 95.3% | -1.2% [-6.3%, 3.9%] |
| LH increase ≤ 1.0 IU/L – Day 85 | 92.5% | 97.4% | -4.9% [-13.6%, 1.4%] |
| LH increase ≤ 1.0 IU/L – Day 169 | 92.4% | 98.6% | -6.2% [-15.3%, -0.1%]* |
1 Serum testosterone < 1.735 nmol/L.
2 Chemical castration was achieved by day 57 in most patients.
3 Kaplan-Meier estimate.
4 A lower bound > -10% demonstrates non-inferiority between treatments.
* 1-month formulation significantly better.
The second phase of study DEB-96-TRI-01 (9 months) compared the efficacy of the 1 month formulation of triptorelin 3.75 mg and the US 1 month formulation of leuprorelin acetate 7.5mg in patients with advanced prostatic cancer (the US formulation of leuprorelin acetate is not the same as the Australian-registered formulation). This study involved 284 patients who had histologically confirmed stage C or D prostatic cancer.
Per protocol and intent-to-treat analyses produced similar results. Whilst the 1-month formulation was slower in inducing chemical castration than the US 1-month leuprorelin acetate formulation, it was non-inferior in maintaining chemical castration (no worse than 10 percentage point difference in incidence) - Table 4.
Table 4. Chemical Castration in Advanced Prostate Cancer Trial DEB-96-TRI-01 Phase 2 per protocol population:
| Parameter | Triptorelin 3.75 mg q 4w (n=135) | Leuprorelin5 7.5 mg q 4w (n=137) | Difference [95% CI]4 |
|---|---|---|---|
| Induction by day 291,2 | 91.1% | 99.3% | -8.2% [-17.1%, 1.4%]* |
| Maintenance 2-9 mths3 | 96.1% | 93.1% | 3.0% [-2.5%, 8.6%] |
| LH increase ≤ 1.0 IU/L – Day 85 | 98.4% | 93.6% | 4.8% [-1.9%, 15.0%] |
| LH increase ≤ 1.0 IU/L – Day 169 | 98.3% | 93.8% | 4.5% [-3.0 , 15.0] |
1 Serum testosterone < 1.735 nmol/L.
2 Chemical castration was achieved by day 57 in most patients.
3 Kaplan-Meier estimate.
4 A lower bound > -10% demonstrates non-inferiority between treatments.
5 US formulation not available in Australia.
* Leuprorelin significantly better.
With continuous use, desensitisation of the pituitary gonadotrophin receptors had generally occurred by 84 days of exposure making a surge in serum testosterone unlikely after this time – Table 3 & Table 4 show that most patients had minimal increases in serum LH (≤ 1.0 IU/L) at days 85 and 169.
In trial DEB-TRI6M-301, 120 patients with advanced prostate cancer received Diphereline 22.5 mg 6-month formulation IM on days 1 and 169 and were followed until Day 337 (48 weeks). The median age of patients was 70 years (range 50 – 92). The primary efficacy endpoints were the percentage of patients achieving the castrate level of testosterone (≤ 1.735 nmol/L) by Day 29 and percentage of patients maintaining this level from day 57 to Week 48. 115 patients (96%) completed the study. Three patients died, one was lost to follow-up and one withdrew consent. Of the patients completing the trial, 93% maintained castrate serum testosterone levels from Day 57 to Week 48 (Table 4 per protocol population). Intent-to-treat results were similar.
Table 5. Chemical Castration in Advanced Prostate Cancer Trial DEB-TRI6M-301 per protocol population:
| Parameter | Triptorelin 22.5 mg q 24w n = 115 | 95% CI |
|---|---|---|
| Induction by Day 291 | 97.4 % | [92.6%, 99.5%] |
| Maintenance 2-9 months2 | 93.9 % | [89.5%, 98.3%] |
| Maintenance 2-12 months (48 weeks)2 | 93.0 % | [88.3%, 97.7%] |
| LH increase ≤ 1.0 IU/L – Day 169 | 98.2 % (n=114) | [93.8%, 99.8%] |
1 Serum testosterone ≤ 1.735 nmol/L.
2 Kaplan-Meier estimate.
Inhibition of the increased hypophyseal gonadotropic activity in children with precocious puberty leads to lowering of the LH levels following GnRH (or GnRH agonist) stimulation test and to suppression of oestradiol and testosterone secretion in girls and boys, respectively.
In a non-comparative clinical study, 44 children with central precocious puberty (39 girls and 5 boys) were treated with a total of two intramuscular injections of Diphereline 22.5 mg over 12 months (48 weeks). Suppression of stimulated LH concentrations to prepubertal levels (serum LH ≤ 5 IU/L) was achieved in 95.5% of subjects by month 3, and in 93.2 % and 97.7% of subjects at months 6 and 12, respectively.
The consequence is a regression or stabilisation of secondary sex characteristics and slowing down of accelerated bone maturation and growth.
In girls, initial ovarian stimulation at treatment initiation, followed by the treatment-induced oestrogen increase, may lead, in the first month, to uterine ‘withdrawal’ bleeding of mild or moderate intensity.
The mean chronological age was 94.6 months (range: 31.0 to 118.0 months). The Tanner stage was stable or reduced in 90.9% of patients between baseline and Month 6 and in 88.6% patients between baseline and Month 12.
Table 6. Tanner Puberty Stage in Precocious Puberty Study:
| Tanner Puberty Stage | ITT n=44 | PP n=43 |
|---|---|---|
| Month 6 (Day 169) | ||
| No increase from baseline 95%CI | 40 / 44 (90.91%) (78.33% ; 97.47%) | 39 / 43 (90.70%) (77.86% ; 97.41%) |
| Month 12 (Day 337) | ||
| No increase from baseline 95%CI | 39 / 44 (88.64%) (75.44%; 96.21%) | 38 / 43 (88.37%) (74.92%; 96.11%) |
The percentage of children with no increase, i.e. reduction or stabilisation, of bone age/chronological age ratio on-treatment was 63.6% at Month 6 and 95.5% at Month 12.
In a sub-study of the pivotal efficacy trial DEB-96-TRI-01 of the 1- and 3-month doses in patients with prostate cancer, triptorelin exposure based on plasma AUC was comparable after intramuscular doses of the 1-month (x 3 doses at 28-day intervals) and 3-month formulations of triptorelin embonate (Table 7). Triptorelin did not accumulate over 9 months of treatment.
In a sub-study in 15 patients with prostate cancer from the efficacy trial of the 6 month formulation (DEB-TRI6M-301), the plasma C max after the first injection was comparable to that obtained previously with the 3-month formulation and higher than the 1-month formulation; however, the AUC over 6 months (resulting from an overall dose of 22.5 mg for all 3 formulations) was about half that after the 3-month and 1-month formulations.
The three sustained release formulations of Diphereline cannot be considered strictly bioequivalent and this is due to differences in polymeric matrix which confers different release rate for each of the three strengths. Nonetheless, the three formulations were demonstrated to be pharmacodynamically equivalent.
The relationship between serum triptorelin and serum testosterone is not linear but on/off, so the level of serum triptorelin rather than AUC is important in maintaining castrate serum testosterone levels. After an initial surge, mean ± SD serum testosterone remained below the castrate level (≤ 1.735 nmol/L) for the 336 days of the trial, except at Day 336 when the upper limit of the standard deviation was above the castrate level.
Table 7. Pharmacokinetic Parameters of 1-Month, 3-Month And 6-Month Formulations of triptorelin embonate:
| Formulation | N | Geometric Mean (range) Cmax after 1st injection (ng/mL) | Median (Range) Tmax after 1st injection (hours) | Geometric Mean AUC over 6 months* (days.ng/mL) |
|---|---|---|---|---|
| 1-month (3.75 mg x 3 doses) | 14 | 15.6 (9.1-25.2) | 2 (2-4) | 197.9 (101.8-452.6) (AUC(169-253d) x 2) |
| 3-month (11.25 mg) | 13 | 35.8 (16.5-57.4) | 2 (1-4) | 202.3 (117.6-325.2) (AUC(169-253d) x 2) |
| 6-month (22.5mg) | 15 | 40.0 (22.2-76.8) | 3 (2-12) | 111.5 (52.2-177.4) AUC169-337d |
* Cumulative AUC over 6 month period (corresponding to 22.5 mg overall: 6 injections of 1-month, 2 injections of 3-month and 1 injection of the 6-month formulation)
In a study in healthy volunteers, the absolute bioavailability of an intramuscular dose of the 1-month formulation was 83%.
In children with precocious puberty median t max was 4 (2-8) hours and C max following the first injection was 39.9 (19.1-107.0) ng/ml.
Results of pharmacokinetic investigations conducted in healthy men indicate that after intravenous bolus administration, triptorelin is distributed and eliminated according to a 3-compartment model and corresponding half-lives are approximately 6 minutes, 45 minutes, and 3 hours.
The volume of distribution at steady state of triptorelin following intravenous administration of 0.5 mg triptorelin is approximately 30 L in healthy male volunteers. Since there is no evidence that triptorelin at clinically relevant concentrations binds to plasma proteins, medicinal product interactions involving binding-site displacement are unlikely.
Metabolites of triptorelin have not been determined in humans. However, human pharmacokinetic data suggest that C-terminal fragments produced by tissue degradation are either completely degraded within tissues or are rapidly further degraded in plasma, or cleared by the kidneys.
Triptorelin is eliminated by both the liver and the kidneys. Following intravenous administration of intermediate-release triptorelin acetate 0.5 mg to 6 young healthy adult males (mean Clcreat 150 mL/min), 42% of the dose was excreted in the urine as intact triptorelin. The mean triptorelin clearance was 212 mL/min.
In the intravenous study referred to under Excretion, patients with renal and liver impairment were also studied. There were 6 subjects in each group. Compared to young healthy adult males, mean triptorelin clearance was reduced by 43% in subjects with moderate renal impairment (mean Clcreat 40 mL/min), 58% in subjects with severe renal impairment (mean Clcreat 8.9 mL/min) and 73% in subjects with hepatic impairment (Child Pugh score 5-9) and a lower mean Clcreat (90 mL/min) than young healthy adult males. Triptorelin exposure was increased 2- to 4-fold in patients with renal or hepatic impairment.
The effects of age and race on triptorelin pharmacokinetics have not been systematically studied. However, pharmacokinetic data obtained in young healthy male volunteers aged 20 to 22 years with an elevated creatinine clearance (approximately 150 mL/min) indicated that triptorelin was eliminated twice as fast in the young population. This is related to the fact that triptorelin clearance is correlated to total creatinine clearance, which is well known to decrease with age.
Because of the large safety margin of triptorelin and since Diphereline is a sustained release formulation, no dose adjustment is recommended in patients with renal or hepatic impairment.
The pharmacokinetics/pharmacodynamics relationship of triptorelin is non-linear and time-dependent. Thus, after acute administration in naive subjects, triptorelin induces a dose- dependent increase of LH and FSH responses.
When administered as a sustained release formulation, triptorelin stimulates LH and FSH secretion during the first days post dosing and, in consequence, testosterone secretion. As shown by the results of the different bioequivalence studies, the maximal increase in testosterone is reached after around 4 days with an equivalent c max which is independent from the release rate of triptorelin. This initial response is not maintained despite continuous exposure to triptorelin and is followed by a progressive decrease of testosterone levels. In this case too, the extent of triptorelin exposure can vary markedly without affecting the overall effect on testosterone serum levels.
In vitro genotoxicity tests for gene mutations and chromosomal damage, and a mouse micronucleus test have provided no evidence for genotoxic effects.
Carcinogenicity studies were conducted in mice (18 months) and rats (23 months) with triptorelin embonate microgranules administered once monthly IM. In mice, no oncogenic effect was observed at triptorelin doses of up to 6000 micrograms/kg/month. In rats, an almost 100% incidence of pituitary tumours was observed at each dose level (120, 600 and 3000 micrograms/kg/month), leading to premature death. There were increased incidences of both pituitary adenomas and carcinomas at all dose levels. The increased incidence of pituitary tumours in rats is a common effect associated with GnRH agonist treatment. The clinical relevance of this is not known.
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