Eligard (Leuprolide Acetate) - Description and Clinical Pharmacology

DESCRIPTION

ELIGARD^® 7.5 mg is a sterile polymeric matrix formulation of leuprolide acetate for subcutaneous injection. It is designed to deliver 7.5 mg of leuprolide acetate at a controlled rate over a one month therapeutic period.

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular and ovarian steroidogenesis. The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula:

ELIGARD^® 7.5 mg is prefilled and supplied in two separate, sterile syringes whose contents are mixed immediately prior to administration. The two syringes are joined and the single dose product is mixed until it is homogenous. ELIGARD^® 7.5 mg is administered subcutaneously where it forms a solid drug delivery depot.

One syringe contains the ATRIGEL^® Delivery System and the other contains leuprolide acetate. The ATRIGEL^® Delivery System is a polymeric (non-gelatin containing) delivery system consisting of a biodegradable poly(DL-lactide-co-glycolide) (PLGH) polymer formulation dissolved in a biocompatible solvent, N -methyl-2-pyrrolidone (NMP). PLGH is a co-polymer with a 50:50 molar ratio of DL-lactide to glycolide containing carboxyl end groups. The second syringe contains leuprolide acetate and the constituted product is designed to deliver 7.5 mg of leuprolide acetate at the time of subcutaneous injection.

ELIGARD^® 7.5 mg delivers 7.5 mg of leuprolide acetate (equivalent to approximately 7.0 mg leuprolide free base) dissolved in 160 mg N -methyl-2-pyrrolidone and 82.5 mg poly(DL-lactide-co-glycolide). The approximate weight of the administered formulation is 250 mg.

CLINICAL PHARMACOLOGY

Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Animal and human studies indicate that after 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.

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 below castrate threshold (</= 50 ng/dL). These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for up to seven years.

PHARMACODYNAMICS

Following the first dose of ELIGARD^® 7.5 mg, mean serum testosterone concentrations transiently increased, then fell to below castrate threshold (</= 50 ng/dL) within three weeks (Figure 1). Continued monthly treatment maintained castrate testosterone suppression throughout the study. No breakthrough of testosterone concentrations above castrate threshold (> 50 ng/dL) occurred at any time during the study once castrate suppression was achieved.

Leuprolide acetate is not active when given orally.

PHARMACOKINETICS

Absorption:    The pharmacokinetics/pharmacodynamics observed during three once monthly injections (ELIGARD^® 7.5 mg) in 20 patients with advanced carcinoma of the prostate is shown in Figure 1. Mean serum leuprolide concentrations following the initial injection rose to 25.3 ng/mL (C_max) at approximately 5 hours after injection. After the initial increase following each injection, serum concentrations remained relatively constant (0.28 - 2.00 ng/mL). There was no evidence of significant accumulation during repeated dosing. Nondetectable leuprolide plasma concentrations have been observed during chronic ELIGARD^® 7.5 mg administration, but testosterone levels were 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.¹ 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 8.34 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.¹

No drug metabolism study was conducted with ELIGARD^® 7.5 mg. Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M-1) metabolite.

Excretion:    No drug excretion study was conducted with ELIGARD^® 7.5 mg.

SPECIAL POPULATIONS:

Geriatrics:    The majority (70%) of the 128 patients studied in these clinical trials were age 70 and older.

Pediatrics:    The safety and effectiveness of ELIGARD^® 7.5 mg in pediatric patients have not been established (see CONTRAINDICATIONS).

Race:    In patients studied (26 White, 2 Hispanic), mean serum leuprolide concentrations were similar.

Renal and Hepatic Insufficiency:    The pharmacokinetics of ELIGARD^® 7.5 mg in hepatically and renally impaired patients have not been determined.

Drug-Drug Interactions:    No pharmacokinetic drug-drug interaction studies were conducted with ELIGARD^® 7.5 mg.

CLINICAL STUDIES

In one open-label, multicenter study (AGL9904), 120 patients with advanced prostate cancer were treated with six monthly injections of ELIGARD^® 7.5 mg. Eighty-nine patients had stage C disease and 31 patients had stage D disease. This study evaluated the achievement and maintenance of serum testosterone suppression over six months of therapy.

The mean testosterone concentration increased from 361.3 ng/dL at Baseline to 574.6 ng/dL at Day 3 following the initial subcutaneous injection. The mean serum testosterone concentration then decreased to below Baseline by Day 10 and was 21.8 ng/dL on Day 28. At the conclusion of the study (Month 6), mean testosterone concentration was 6.1 ng/dL (Figure 2).

Serum testosterone was suppressed to below the castrate threshold (</= 50 ng/dL) by Day 28 (Week 4) in 112 of 119 (94.1%) patients remaining in the study. The remaining seven patients all attained the castrate threshold by Day 42. Once testosterone suppression at or below serum concentrations of 50 ng/dL was achieved, no patients (0%) demonstrated breakthrough (concentration above 50 ng/dL) at any time in the study. All 117 evaluable patients in the study at Month 6 (two patients withdrew for reasons unrelated to drug) had testosterone concentrations of </= 50 ng/dL.

Serum PSA decreased in all patients whose Baseline values were elevated above the normal limit. Mean values were reduced 94% from Baseline to Month 6. At Month 6, PSA levels had decreased to within normal limits in 94% of patients who presented with elevated levels at Baseline.

Other secondary efficacy endpoints evaluated included WHO performance status, bone pain, urinary pain and urinary signs and symptoms. At Baseline, 88% of patients were classified as "fully active" by the WHO performance status scale (Status=0) and 11% as "restricted in strenuous activity but ambulatory and able to carry out work of a light or sedentary nature" (Status=1). These percentages were unchanged at Month 6. At Baseline, patients experienced little bone pain, with a mean score of 1.22 (range 1-9) on a scale of 1 (no pain) to 10 (worst pain possible). At Month 6, the mean bone pain score was essentially unchanged at 1.26 (range 1-7). Urinary pain, scored on the same scale, was similarly low, with a mean of 1.12 at Baseline (range 1-5) and 1.07 at Month 6 (range 1-8). Urinary signs and symptoms were similarly low at Baseline and decreased modestly at Month 6. In addition, there was a reduction in patients with prostate abnormalities detected during physical exam from 102 (85%) at Screening to 77 (64%) at Month 6.