Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: AbbVie (Pty) Ltd, Abbott Place, 219 Golf Club Terrace, Constantia Kloof, 1709
A 21.10 – Tropic hormones
Leuprolide acetate is a synthetic nonapeptide analogue of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH).
Leuprolide acetate, a GnRH agonist, acts as an inhibitor of gonadotropin. Animal and human studies indicate that following an initial stimulation, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroideogenesis. This effect is reversible on discontinuation of therapy.
Administration of leuprolide acetate results in an initial increase in circulating levels of luteinising hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in pre-menopausal females).
However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH and sex steroids. In males, testosterone is reduced to castration or prepubertal levels. In pre-menopausal females, oestrogens are reduced to post-menopausal levels. During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of LUCRIN DEPOT 3,75. These hormonal changes occur within a month of initiating medicine therapy at recommended doses.
In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females respectively. Reduction of gonadotropins will allow for normal growth and development. Natural maturation occurs when gonadotropins return to pubertal levels following discontinuation of leuprolide acetate.
In patients with metastatic castration-resistant prostate cancer, clinical studies have shown benefit from the addition of medicines such as the androgen axis inhibitors abiraterone acetate and enzalutamide, the taxanes docetaxel and cabazitaxel, and the radiopharmaceutical Ra-223 to GnRH agonists such as leuprorelin.
Leuprolide acetate is not active when given orally. Bioavailability of leuprolide acetate following subcutaneous administration is comparable to that after intramuscular administration.
Absorption
Following a single administration of leuprolide acetate for depot suspension in prostatic carcinoma patients, doses of 3,75 mg and 7,5 mg by subcutaneous and intramuscular routes provided mean leuprolide acetate plasma concentrations at the end of one month of 0,7 ng/mL and 1,0 ng/mL, respectively. There was no indication of any medicine accumulation.
Serum levels of leuprolide acetate 3,75 mg were measured in 11 patients with premenopausal breast cancer over 12 weeks.
Mean leuprolide acetate levels were above 0, 1 ng/mL after four weeks and remained stable after re-injection (at 8 and 12 weeks). There was no tendency for medicine accumulation.
Distribution
The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43 % to 49 %.
Metabolism
In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously, revealed that the mean systemic clearance was 7,6 L/h, with a terminal elimination half-life of approximately three hours based on a two compartment model.
Animal studies have shown 14C-labeled leuprolide was metabolised into smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further metabolised.
The major metabolite (M-I) plasma concentrations measured in five prostate cancer patients given leuprolide acetate depot suspension reached a maximum concentration two to six hours after dosing and were approximately 6 % of the peak parent medicine concentration.
One week after dosing, mean plasma M-I concentrations were approximately 20 % of mean leuprolide concentrations.
Excretion
Following administration of leuprolide acetate for depot suspension 3,75 mg to three patients, less than 5 % of the dose was recovered as parent and M-I metabolite in the urine over 27 days.
Special Populations
The pharmacokinetics of this product has not been determined in patients with hepatic or renal impairment.
Paediatric Patients
In a study of 22 children with central precocious puberty, doses of leuprolide acetate for Depot Suspension were given every four weeks and plasma levels were determined according to weight categories as summarised below.
| Patient Weight Range (kg) | Group Weight Average (kg) | Dose (mg) | Trough Plasma Leuprolide Level mean ± SD (ng/mL)* |
|---|---|---|---|
| 20,2-27,0 | 22,7 | 7,5 | 0,77 ± 0,33 |
| 28,4-36,8 | 32,5 | 11,25 | 1,25 ± 1,06 |
| 39,3-57,5 | 44,2 | 15,0 | 1,59 ± 0,65 |
* Group average values determined at Week 4 immediately prior to leuprolide injection. Medicine levels at 12 and 24 weeks were similar to respective 4-week levels
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