Triptorelin

Triptorelin, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies show that after administration of triptorelin there is an initial and transient increase in circulating levels of luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone in males and oestradiol in females.

However, chronic and continuous administration of triptorelin results in decreased LH and FSH secretion and suppression of testicular and ovarian steroidogenesis.

Triptorelin is a synthetic decapeptide analogue of the natural gonadotrophin-releasing hormone (GnRH). GnRH is a decapeptide, which is synthesised in the hypothalamus and regulates the biosynthesis and release of the gonadotrophins LH (luteinising hormone) and FSH (follicle stimulating hormone) by the pituitary.

Triptorelin stimulates the pituitary more strongly to secretion of LH and FSH than a comparable dose of gonadorelin, whereas the duration of action is longer. The increase of LH and FSH levels will initially lead to an increase of serum testosterone concentrations in men or serum estrogen concentrations in women. Chronic administration of a GnRH agonist results in an inhibition of pituitary LH- and FSH-secretion. This inhibition leads to a reduction in steroidogenesis, by which the serum estradiol concentration in women and the serum testosterone concentration in men fall to within the postmenopausal or castrate range, respectively, i.e. a hypogonadotrophic hypogonadal state.

In children with precocious puberty, the concentration of estradiol or testosterone will decrease to within the prepubertal range. Plasma DHEAS (dihydroepiandrostenedion sulphate) levels are not influenced. Therapeutically, this leads to a decrease in growth of testosterone-sensitive prostate tumours in men, and to reduction of endometriosis foci and estrogen-dependent uterus myomas in women. Regarding uterine myoma, maximal benefit of treatment is observed in women with anemia (hemoglobin inferior or equal to 8 g/dl).

In children suffering from CPP triptorelin treatment leads to a suppression of the secretion of gonadotropins, estradiol, and testosterone to prepubertal levels. This results in arrest or even regression of pubertal signs and an increase in adult height prediction in CPP patients.

In healthy volunteers

Subcutaneous administration

Subcutaneously administered triptorelin (100 μg) is rapidly absorbed (T_max = 0.63 ± 0.26 hr for peak plasma concentration = 1.85 ± 0.23 ng/mL). Elimination is effected with a biological half-life of 7.6 ± 1.6 hr, after a 3 to 4 hr distribution phase. Total plasma clearance is: 161 ± 28 mL/min. Distribution volume is 104.1 ± 11.7 litres.

In patients with endometriosis and uterine fibroids

Intramuscular administration

After intramuscular injection of Decapeptyl SR 3 mg in women with endometriosis and uterine fibroids the maximum blood level of triptorelin is obtained between 2 to 6 hours after injection, the peak value reached is 11 ng/mL. There was no evidence of accumulation of the product following monthly injections over six months.

The minimum blood level oscillates between 0.1 and 0.2 ng/mL. The bioavailability of the sustained release product is approximately 50%.

Trough plasma concentrations are maintained between 0.1 and 0.2 ng/mL. The bioavailability of the sustained release product is approximately 50%. These data observed in endometriosis and uterine fibroma patients can be extrapolated to breast cancer patients as it is not expected that the disease has an impact on the prolonged release properties of the product.

In patients with prostate cancer

Subcutaneous administration

With subcutaneous administration (100 μg), triptorelin blood levels oscillate between maximum values of 1.28 ± 0.24 ng/mL (C_max) obtained in general one hour after injection (T_max) and minimum values of 0.28 ± 0.15 ng/mL (C_max) obtained 24hrs after injection.

The biological half-life is on average 11.7 ± 3.4 hr but varies according to patients. Plasma clearance (118 ± 32 mL/min) reflects slower elimination in patients, whilst distribution volumes are close to those of healthy volunteers (113.4 ± 21.6 litres).

Intramuscular administration

Following intramuscular injection of the sustained release form, an initial phase of release of the active principle present on the surface of the microspheres is observed, followed by further fairly regular release (C_max = 0.32 ± 0.12 ng/mL), with a mean rate of release of triptorelin of 46.6 ± 7.1 μg/day. The bioavailability of the microparticles is approximately 53% at one month.

Preclinical findings were only those related to the expected pharmacological activity of triptorelin, namely down-regulation of the hypothalamic-pituitary-gonadal axis. These included atrophy of the testes and genital tract, with resultant suppression of spermatogenesis, together with decreased weight of the prostate gland. These findings were largely reversible within the recovery period. In a small number of rats, in a 24 months oncogenicity study, a low incidence of benign histological changes were seen in the non-glandular part of the fore stomach. Erosions, ulcers, necrosis and inflammation were seen at varying degrees of severity. The clinical relevance of these findings is unknown. The increased incidence of adenomatous tumours in the rat pituitary observed with Decapeptyl following long-term repeated dosing is thought to be a class specific action of GnRH analogues due to a hormonally-mediated mechanism and has not been found in the mouse nor has it been described in man.

Triptorelin has been shown to be embryo-/foetotoxic and to cause a delay in embryo-/foetal development as well as delay in parturition in rats. Preclinical data reveal no special hazard to humans based on repeat dose toxicity and genotoxicity studies. Single I.M. or S.C. injection of GONAPEPTYL Depot or its suspension agent produced delayed foreign body reactions at the injection site. Within 8 weeks, these late reactions were nearly reversed after I.M. injection but only slightly reversed after S.C. injection. Local tolerance of Gonapeptyl Depot after I.V. injection was limited.