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Lupron Depot 7.5

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Lupron Depot 7.5 mg

Lupron Depot 7.5 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion. Animal studies indicate that following an initial stimulation, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy.

Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.

Pharmacodynamics

In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing 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 premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. In premenopausal females, estrogens are reduced to postmenopausal levels. These decreases occur within two to four weeks after initiation of treatment, and castrate levels of testosterone in prostatic cancer patients have been demonstrated for more than five years.

Leuprolide acetate is not active when given orally.

Pharmacokinetics

Absorption

Following a single injection of LUPRON DEPOT 7.5 mg for 1-month administration to patients, mean plasma leuprolide concentration was almost 20 ng/mL at 4 hours and 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 an open-label, non-comparative, multicenter clinical study of LUPRON DEPOT 7.5 mg for 1month administration, 56 patients with stage D2 prostatic adenocarcinoma and no prior systemic treatment were enrolled. The objectives were to determine if a 7.5 mg depot formulation of leuprolide injected once every 4 weeks would reduce and maintain serum testosterone to castrate range ( ≤ 50 ng/dL), to evaluate objective clinical response, and to assess the safety of the formulation. During the initial 24 weeks, serum testosterone was measured weekly, biweekly, or every four weeks and objective tumor response assessments were performed at Weeks 12 and 24. Once the patient completed the initial 24-week treatment phase, treatment continued at the investigator's discretion. Data from the initial 24-week treatment phase are summarized in this section.

In the majority of patients, serum testosterone increased by 50% or more above baseline during the first week of treatment. Serum testosterone suppressed to the castrate range within 30 days of the initial depot injection in 94% (51/54) of patients for whom testosterone suppression was achieved (2 patients withdrew prior to onset of suppression) and within 66 days in all 54 patients. Mean serum testosterone suppressed to castrate level by Week 3. The median dosing interval between injections was 28 days. One escape from suppression (2 consecutive testosterone values greater than 50 ng/dL after achieving castrate level) was noted at Week 18, associated with a substantial dosing delay. In this patient, serum testosterone returned to the castrate range at the next monthly measurement. Serum testosterone was minimally above the castrate range on a single occasion for 4 other patients. No clinical significance was attributed to these rises in testosterone.

Lupron Depot 7.5 mg Mean Serum Testosterone Concentrations

Mean Serum Testosterone Concentrations - Illustration

Secondary efficacy endpoints evaluated included objective tumor response, assessed by clinical evaluations of tumor burden (complete response, partial response, objectively stable, and progression), as well as changes in local disease status, assessed by digital rectal examination, and changes in prostatic acid phosphatase (PAP). These evaluations were performed at Weeks 12 and 24. The objective tumor response analysis showed a “no progression” (ie. complete or partial response, or stable disease) in 77% (40/52) of patients at Week 12, and in 84% (42/50) of patients at Week 24. Local disease improved or remained stable in all (42) patients evaluated at Week 12 and in 98% (41/42) of patients elevated at Week 24. PAP normalized or decreased at Week 12 and/or 24 in the majority of patients with elevated baseline PAP.

Periodic monitoring of serum testosterone and PSA levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

Last reviewed on RxList: 7/24/2013
This monograph has been modified to include the generic and brand name in many instances.

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