Zoladex Mechanism of Action

Pharmacology: Pharmacodynamics: ZOLADEX (D-Ser (Bu^t)⁶ Azgly¹⁰ LHRH) is a synthetic analogue of naturally occurring LHRH. On chronic administration ZOLADEX results in inhibition of pituitary LH secretion leading to a fall in serum testosterone concentrations in males and serum oestradiol concentrations in females. This effect is reversible on discontinuation of therapy. Initially, ZOLADEX, like other LHRH agonists, may transiently increase serum testosterone concentration in men and serum oestradiol concentration in women. During early treatment with ZOLADEX some women may experience vaginal bleeding of variable duration and intensity. Such bleeding probably represents oestrogen withdrawal bleeding and is expected to stop spontaneously.
In men by around 21 days after the first depot injection testosterone concentrations have fallen to within the castrate range and remain suppressed with continuous treatment every 28 days. This inhibition leads to prostate tumour regression and symptomatic improvement in the majority of patients.
In women serum oestradiol concentrations are suppressed by around 21 days after the first depot injection and, with continuous treatment every 28 days, remain suppressed at levels comparable with those observed in postmenopausal women. This suppression is associated with a response in hormone dependent breast cancer, endometriosis, uterine fibroids and suppression of follicular development within the ovary. It will produce endometrial thinning and will result in amenorrhoea in the majority of patients.
ZOLADEX in combination with iron has been shown to induce amenorrhoea and improve haemoglobin concentrations and related haematological parameters in women with fibroids who are anaemic. The combination produced a mean haemoglobin concentration 1g/dl above that achieved by iron therapy alone.
During treatment with LHRH analogues patients may enter the menopause. Rarely, some women do not resume menses on cessation of therapy.
Pharmacokinetics: The bioavailability of ZOLADEX mg is almost complete. Administration of a depot every four weeks ensures that effective concentrations are maintained with no tissue accumulation. ZOLADEX is poorly protein bound and has a serum elimination half-life of two to four hours in subjects with normal renal function. The half-life is increased in patients with impaired renal function. For the compound given monthly in a depot formulation, this change will have minimal effect. Hence, no change in dosing is necessary in these patients. There is no significant change in pharmacokinetics in patients with hepatic failure.
Toxicology: Preclinical safety data: Following long-term repeated dosing with ZOLADEX, an increased incidence of benign pituitary tumours has been observed in male rats. Whilst this finding is similar to that previously noted in this species following surgical castration, any relevance to humans has not been established.
In mice, long term repeated dosing with multiples of the human dose produced histological changes in some regions of the digestive system manifested by pancreatic islet cell hyperplasia and a benign proliferative condition in the pyloric region of the stomach, also reported as a spontaneous lesion in this species. The clinical relevance of these findings is unknown.