Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin
secretion when given continuously and in therapeutic doses. Human studies indicate
that following an initial stimulation of gonadotropins, chronic stimulation
with leuprolide acetate results in suppression or "downregulation"
of these hormones and consequent suppression of ovarian and testicular steroidogenesis.
These effects are reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally.
Pharmacokinetics
Absorption
Following a single LUPRON DEPOT 7.5 mg injection to adult patients, mean peak
leuprolide plasma concentration was almost 20 ng/mL at 4 hours and then declined
to 0.36 ng/mL at 4 weeks. However, intact leuprolide and an inactive major metabolite
could not be distinguished by the assay which was employed in the study. Nondetectable
leuprolide plasma concentrations have been observed during chronic LUPRON DEPOT
7.5 mg administration, but testosterone levels appear to be maintained at castrate
levels.
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 3 hours based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown
to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I),
tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These
fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer
patients reached maximum concentration 2 to 6 hours after dosing and were approximately
6% of the peak parent drug concentration. One week after dosing, mean plasma
M-I concentrations were approximately 20% of mean leuprolide concentrations.
Excretion
Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5%
of the dose was recovered as parent and M-I metabolite in the urine.
Special Populations
The pharmacokinetics of the drug in hepatically and renally impaired patients
have not been determined.
Clinical Studies
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 physical and psychological growth and development. Natural
maturation occurs when gonadotropins return to pubertal levels following discontinuation
of leuprolide acetate. The following physiologic effects have been noted with
the chronic administration of leuprolide acetate in this patient population.
- Skeletal Growth. A measurable increase in body length can be noted
since the epiphyseal plates will not close prematurely.
- Organ Growth. Reproductive organs will return to a prepubertal state.
- Menses. Menses, if present, will cease.
In a study of 22 children with central precocious puberty, doses of LUPRON
DEPOT were given every 4 weeks and plasma levels were determined according to
weight categories as summarized 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±0.033 |
| 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. Drug levels at 12 and 24 weeks were similar to
respective 4 week levels. |
Last updated on RxList: 1/22/2009