Mechanism of Action
SUPPRELIN LA is a GnRH agonist and an inhibitor of gonadotropin secretion when given continuously. It delivers approximately 65 mcg histrelin per day. Both animal and human studies indicate that following an initial stimulatory phase, chronic, subcutaneous administration of histrelin desensitizes responsiveness of the pituitary gonadotropin which, in turn causes a reduction in ovarian and testicular steroidogenesis.
In humans, administration of histrelin acetate results in an initial increase in circulating levels of LH and FSH, leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females).
However, continuous administration of histrelin acetate causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. These inhibitory effects result in decreased levels of LH and FSH.
Long-term treatment with histrelin suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Consequently, secondary sexual development ceases to progress in most patients. Additionally, linear growth velocity is slowed which improves the chance of attaining predicted adult height.
Pharmacokinetics of histrelin after implantation of SUPPRELIN LA was evaluated in a total of 47 children with CPP (11 subjects in Study 1 and 36 subjects in Study 2). Patients were examined at 4 weeks after implant insertion and a few times throughout the treatment period. Median serum histrelin concentrations remained above the limit of quantification for the treatment period. Histrelin acetate levels were sustained throughout the study period for most subjects (Figure 3). The median of maximum serum histrelin concentrations over the study period was 0.43 ng/mL, which is expected to maintain gonadotropins at prepubertal levels. There was no apparent pharmacokinetic difference between naïve subjects to a LHRH agonist treatment and subjects who had previous treatment with a LHRH agonist (Figure 3).
Figure 3. Mean and Standard Deviation of Serum Histrelin Concentrations (ng/mL) Results at Each Visit
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in rats for 2 years at doses of 5, 25 or 150 mcg/kg/day (up to 11 times human exposures using body surface area comparisons, based on a 65 mcg/day dose in humans) and in mice for 18 months at doses of 20, 200, or 2000 mcg/kg/day (at less than therapeutic exposure to 70 times human exposure using body surface area comparisons, based on a 65 mcg/day dose in humans). As seen with other GnRH agonists, histrelin injection administration was associated with an increase in tumors of hormonally responsive tissues. There was a significant increase in pituitary adenomas in rats at mid and high doses (2-11 times human exposure based on body surface area comparisons with a 65 mcg/day human dose). There was an increase in pancreatic islet-cell adenomas in treated female rats and a non-dose-related increase in testicular Leydig-cell tumors (highest incidence in the low-dose group). In mice, there was significant increase in mammary-gland adenocarcinomas in all treated females. In addition, there were increases in stomach papillomas in male rats given high doses, and an increase in histiocytic sarcomas in female mice at the highest dose.
Mutagenicity studies have not been performed with histrelin acetate. Saline extracts of implants with and without histrelin acetate were negative in a battery of genotoxicity studies. Fertility studies have been conducted in rats and monkeys given subcutaneous daily doses of histrelin acetate up to 180 mcg/kg/day (up to 13 and 30 times human exposure, respectively using body surface area comparisons, based on a 65 mcg/day human dose) for 6 months and full reversibility of fertility suppression was demonstrated. The development and reproductive performance of offspring from parents treated with histrelin acetate has not been investigated.