Goserelin - How It Works
Clinical pharmacology details from the US FDA-approved label: how Goserelin works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action ZOLADEX is a synthetic decapeptide analogue of GnRH. ZOLADEX acts as an inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation. In animal and in vitro studies, administration of goserelin resulted in the regression or inhibition of growth of the hormonally sensitive dimethylbenzanthracene (DMBA)-induced rat mammary tumor and Dunning R3327 prostate tumor.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ZOLADEX is a synthetic decapeptide analogue of GnRH.
ZOLADEX acts as an inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation.
In animal and in vitro studies, administration of goserelin resulted in the regression or inhibition of growth of the hormonally sensitive dimethylbenzanthracene (DMBA)-induced rat mammary tumor and Dunning R3327 prostate tumor.
12.2 Pharmacodynamics Following initial administration in males, ZOLADEX causes an initial increase in serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels with subsequent increases in serum levels of testosterone.
Chronic administration of ZOLADEX leads to sustained suppression of pituitary gonadotropins, and serum levels of testosterone consequently fall into the range normally seen in surgically castrated men approximately 2-4 weeks after initiation of therapy.
This leads to accessory sex organ regression.
In clinical trials with follow-up of more than 2 years, suppression of serum testosterone to castrate levels has been maintained for the duration of therapy.
In females, a similar down-regulation of the pituitary gland by chronic exposure to ZOLADEX leads to suppression of gonadotropin secretion, a decrease in serum estradiol to levels consistent with the postmenopausal state, and would be expected to lead to a reduction of ovarian size and function, reduction in the size of the uterus and mammary gland, as well as a regression of sex hormone-responsive tumors, if present.
Serum estradiol is suppressed to levels similar to those observed in postmenopausal women within 3 weeks following initial administration; however, after suppression was attained, isolated elevations of estradiol were seen in 10% of the patients enrolled in clinical trials.
Serum LH and FSH are suppressed to follicular phase levels within four weeks after initial administration of drug and are usually maintained at that range with continued use of ZOLADEX.
In 5% or less of women treated with ZOLADEX, FSH and LH levels may not be suppressed to follicular phase levels on day 28 post treatment with use of a single 3.6 mg depot injection.
In certain individuals, suppression of any of these hormones to such levels may not be achieved with ZOLADEX.
Estradiol, LH and FSH levels return to pretreatment values within 12 weeks following the last implant administration in all but rare cases.
12.3 Pharmacokinetics The pharmacokinetics of ZOLADEX have been determined in both male and female healthy volunteers and patients.
In these studies, ZOLADEX was administered as a single 250 mcg (aqueous solution) dose and as a single or multiple 3.6 mg depot dose by subcutaneous route.
Absorption The absorption of radiolabeled drug was rapid, and the peak blood radioactivity levels occurred between 0.5 and 1.0 hour after dosing.
The mean (± standard deviation) pharmacokinetic parameter estimates of ZOLADEX after administration of 3.6 mg depot for 2 months in males and females are presented in the following table.
Table 7 PHARMACOKINETIC PARAMETER ESTIMATES Parameter (units) Males n=7 Females n=9 Peak Plasma Concentration (ng/mL) 2.84 ± 1.81 1.46 ± 0.82 Time to Peak Concentration (days) 12-15 8-22 Area Under the Curve (0-28 days) (ng.d/mL) 27.8 ± 15.3 18.5 ± 10.3 Systemic Clearance (mL/min) 110.5 ± 47.5 163.9 ± 71.0 Goserelin is released from the depot at a much slower rate initially for the first 8 days, and then there is more rapid and continuous release for the remainder of the 28-day dosing period.
Despite the change in the releasing rate of goserelin, administration of ZOLADEX every 28 days resulted in testosterone levels that were suppressed to and maintained in the range normally seen in surgically castrated men.
When ZOLADEX 3.6 mg depot was used for treating male and female patients with normal renal and hepatic function, there was no significant evidence of drug accumulation.
Pharmacokinetics
12.3 Pharmacokinetics The pharmacokinetics of ZOLADEX have been determined in both male and female healthy volunteers and patients. In these studies, ZOLADEX was administered as a single 250 mcg (aqueous solution) dose and as a single or multiple 3.6 mg depot dose by subcutaneous route. Absorption The absorption of radiolabeled drug was rapid, and the peak blood radioactivity levels occurred between 0.5 and 1.0 hour after dosing. The mean (± standard deviation) pharmacokinetic parameter estimates of ZOLADEX after administration of 3.6 mg depot for 2 months in males and females are presented in the following table. Table 7 PHARMACOKINETIC PARAMETER ESTIMATES Parameter (units) Males n=7 Females n=9 Peak Plasma Concentration (ng/mL) 2.84 ± 1.81 1.46 ± 0.82 Time to Peak Concentration (days) 12-15 8-22 Area Under the Curve (0-28 days) (ng.d/mL) 27.8 ± 15.3 18.5 ± 10.3 Systemic Clearance (mL/min) 110.5 ± 47.5 163.9 ± 71.0 Goserelin is released from the depot at a much slower rate initially for the first 8 days, and then there is more rapid and continuous release for the remainder of the 28-day dosing period. Despite the change in the releasing rate of goserelin, administration of ZOLADEX every 28 days resulted in testosterone levels that were suppressed to and maintained in the range normally seen in surgically castrated men. When ZOLADEX 3.6 mg depot was used for treating male and female patients with normal renal and hepatic function, there was no significant evidence of drug acc