Clinical Pharmacology

Clinical Pharmacology

Mechanism of action

Leuprolide acetate, a gonadotropin releasing hormone (GnRH) 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 doses.

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 testosteronesuppression 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

During the pharmacokinetic plateau phase (days 7–168), median leuprolide acetate concentrations range from 0.1 to 3.0 ng/mL after the first dose is administered. The safety and efficacy of the four different dose levels have been established in clinical trials for approval by regulatory authorities in the USA. ^[1]

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 (C_max) at approximately five (5) hours after injection. After the initial increase following each injection, serum concentrations remained relatively constant (0.28 – 2.00 ng/mL).

A reduced number of sampling time points resulted in the apparent decrease in C_max values with the second and third doses of ELIGARD 7.5 mg (Figure 1).

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ELIGARD 22.5 mg

The pharmacokinetics/pharmacodynamics observed during two injections every three months (ELIGARD 22.5 mg) in 22 patients with advanced prostate cancer is shown in Figure 2.

Mean serum leuprolide concentrations rose to 127 ng/mL and 107 ng/mL at approximately five (5) hours following the initial and second injections, respectively. After the initial increase following each injection, serum concentrations remained relatively constant (0.2 – 2.0 ng/mL).

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ELIGARD 30 mg

The pharmacokinetics/pharmacodynamics observed during injections administered initially and at four months (ELIGARD 30 mg) in 24 patients with advanced prostate cancer is shown in Figure 3.

Mean serum leuprolide concentrations following the initial injection rose rapidly to 150 ng/mL (C_max) at approximately 3.3 hours after injection. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.1 – 1.0 ng/mL).

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ELIGARD 45 mg

The pharmacokinetics/pharmacodynamics observed during injections administered initially and at six months (ELIGARD 45 mg) in 27 patients with advanced prostate cancer is shown in Figure 4.

Mean serum leuprolide concentrations rose to 82 ng/mL and 102 ng/mL (C_max) at approximately 4.5 hours following the initial and second injections, respectively. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.2 – 2.0 ng/mL).

There was no evidence of significant accumulation during repeated dosing. Non-detectable leuprolide plasma concentrations have been occasionally observed during ELIGARD administration, but testosterone levels were maintained at castrate levels.

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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 8.34 L/h, with a terminal elimination half-life of approximately three (3) hours based on a two compartment model.

No drug metabolism study was conducted with ELIGARD. 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.

Geriatrics

See Use in Specific populations.

Race

In patients studied, mean serum leuprolide concentrations were similar regardless of race. Refer to Table 7 for distribution of study patients by race.

Renal and hepatic insufficiency

The pharmacokinetics of ELIGARD in hepatically and renally impaired patients have not been determined.

References

1. Shore N, et al., BJU Int. 2016