Pharmacokinetic data were obtained using a nonspecific RIA method.

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. However, in clinical trials the minimum serum levels of a few patients were increased. These levels can be attributed to interpatient variation.

Distribution: The apparent volumes of distribution determined after subcutaneous administration of 250 µg aqueous solution of goserelin were 44.1 and 20.3 liters for males and females, respectively. The plasma protein binding of goserelin obtained from one sample was found to be 27.3%.

Metabolism: Metabolism of goserelin, by hydrolysis of the C-terminal amino acids, is the major clearance mechanism. The major circulating component in serum appeared to be 1-7 fragment, and the major component presented in urine of one healthy male volunteer was 5-10 fragment. The metabolism of goserelin in humans yields a similar but narrow profile of metabolites to that found in other species. All metabolites found in humans have also been found in toxicology species.

Excretion: Clearance of goserelin following subcutaneous administration of the solution formulation of goserelin is very rapid and occurs via a combination of hepatic metabolism and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin is excreted in urine. Approximately 20% of the dose in urine is accounted for by unchanged goserelin. The total body clearance of goserelin (administered subcutaneously as a 3.6 mg depot) was significantly (p<0.05) greater (163.9 versus 110.5 mL/min) in females compared to males.

Special Populations

Renal Insufficiency: In clinical trials with the solution formulation of goserelin, male patients with impaired renal function (creatinine clearance < 20 mL/min) had a total body clearance and serum elimination half-life of 31.5 mL/min and 12.1 hours, respectively, compared to 133 mL/min and 4.2 hours for subjects with normal renal function (creatinine clearance > 70 mL/min). In females, the effects of reduced goserelin clearance due to impaired renal function on drug efficacy and toxicity are unknown. Pharmacokinetic studies using the aqueous formulation of goserelin in patients with renal impairment do not indicate a need for dose adjustment with the use of the depot formulation.

Hepatic Insufficiency: The total body clearances and serum elimination half-lives were similar between normal and hepatic impaired patients receiving 250 µg solution formulation of goserelin. Pharmacokinetic studies using the aqueous formulation of goserelin in patients with hepatic impairment do not indicate a need for dose adjustment with the use of the depot formulation.

Drug-Drug Interactions: No formal drug-drug interaction studies have been performed.

Clinical Studies

Prostatic Carcinoma: In controlled studies of patients with advanced prostatic cancer comparing ZOLADEX to orchiectomy, the long-term endocrine responses and objective responses were similar between the two treatment arms. Additionally, duration of survival was similar between the two treatment arms in a comparative trial.

Stage B2-C Prostatic Carcinoma: The effects of hormonal treatment combined with radiation were studied in 466 patients (231 ZOLADEX + flutamide + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement.

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