Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2015 Publisher: Ferring Pharmaceuticals Ltd., Drayton Hall, Church Road, West Drayton, UB7 7PS, United Kingdom
Pharmacotherapeutic group: Gonadorelinanaloga
ATC code: L02AE04
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.
After intramuscular administration of GONAPEPTYL Depot, the plasma concentrations of triptorelin are determined by the (slow) degradation of the poly-(d,l lactide coglycolide) polymer. The mechanism inherent to this administration form enables this slow release of triptorelin from the polymer.
After I.M. or S.C. application of a triptorelin depot-formulation (sustained-release microcapsules), a rapid increase in the concentration of triptorelin in plasma is recorded, with a maximum in the first hours. Then the triptorelin concentration declines notably within 24 hours. On day 4 the value reaches a second maximum, falling below the detection limit in a biexponential course after 44 days. After S.C. injections the triptorelin increase is more gradual and in a somewhat lower concentration than after I.M. injections. After S.C. injection, the decline in the triptorelin concentration takes longer, with values falling below the detection limit after 65 days.
During treatment over a period of 6 months and an administration every 28 days, there was no evidence of triptorelin accumulation in both modes of administration. Plasma triptorelin values decreased to approx. 100 pg/ml before the next application after I.M. or S.C. application (median values). It is to be assumed that the non-systemically available proportion of triptorelin is metabolized at the injection site, e.g. by macrophages.
In the pituitary, the systemically available triptorelin is inactivated by N-terminal cleavage via pyroglutamyl-peptidase and a neutral endopeptidase. In the liver and the kidneys, triptorelin is degraded to biologically inactive peptides and amino acids.
40 minutes after the end of an infusion of 100 µg triptorelin (over 1 hour) 3-14% of the administered dose has already been eliminated by the kidney.
For patients with an impaired renal function, adaptation and individualization of therapy with the triptorelin depot-formulation seems to be unnecessary, on account of the subordinate significance of the renal elimination route and the broad therapeutic range of triptorelin as an active component.
The systemic bioavailability of the active component triptorelin from the intramuscular depot is 38.3% in the first 13 days. Further release is linear at 0.92% of the dose per day on average. Bioavailability after S.C. application is 69% of I.M. availability.
After 27 test days, 35.7% of the applied dose can be detected on average, with 25.5% being released in the first 13 days and further release being linear at 0.73% of the dose per day on average.
Calculation of the model-depending kinetic parameters (t½, Kel, etc.) is inapplicable in presentations with a strongly protracted release of the active component.
In rats, but not in mice treated over a long period of time with triptorelin, an increase in pituitary tumors has been detected. The influence of triptorelin on pituitary abnormalities in humans is unknown. The observation is considered not to be relevant to humans. Pituitary tumors in rodents in connection with other LHRH analogues have also been known to occur. 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.
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