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 testicular and ovarian 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®, mean serum testosterone concentrations transiently increased, then fell to below castrate threshold ( ≤ 50 ng/dL) within three weeks for all ELIGARD® concentrations.

Continued monthly treatment with ELIGARD® 7.5 mg 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 (Figure 1).

One patient received less than a full dose of ELIGARD® 22.5 mg at baseline, never suppressed and withdrew from the study at Day 73. Of the 116 patients remaining in the study, 115 (99%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 35, 116 (100%) had serum testosterone levels below the castrate threshold. Once testosterone suppression was achieved, one patient ( < 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) following the initial injection; that patient remained below the castrate threshold following the second injection (Figure 2).

One patient withdrew from the ELIGARD® 30 mg study at Day 14. Of the 89 patients remaining in the study, 85 (96%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 42, 89 (100%) of patients attained castrate testosterone suppression. Once castrate testosterone suppression was achieved, three patients (3%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (Figure 3).

One patient at Day 1 and another patient at Day 29 were withdrawn from the ELIGARD® 45 mg study. Of the 109 patients remaining in the study, 108 (99.1%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). One patient did not achieve castrate suppression and was withdrawn from the study at Day 85. Once castrate testosterone suppression was achieved, one patient ( < 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (Figure 4).

Leuprolide acetate is not active when given orally.

Pharmacokinetics

Absorption

ELIGARD® 7.5 mg

The pharmacokinetics/pharmacodynamics observed during three once-monthly injections in 20 patients with advanced prostate cancer is shown in Figure 1. Mean serum leuprolide concentrations following the initial injection rose to 25.3 ng/mL (Cmax) at approximately 5 hours after injection. After the initial increase following each injection, serum concentrations remained relatively constant (0.28 - 2.00 ng/mL).

Figure 1 - Pharmacokinetic/Pharmacodynamic Response (N=20) to ELIGARD® 7.5 mg - Patients Dosed Initially and at Months 1 and 2

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