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

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 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).

Figure 2 - Pharmacokinetic/Pharmacodynamic Response (N=22) to ELIGARD® 22.5 mg - Patients Dosed Initially and at Month 3

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 (Cmax) 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).

Figure 3 -Pharmacokinetic/Pharmacodynamic Response (N=24) to ELIGARD® 30 mg - Patients Dosed Initially and at Month 4

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 82.0 ng/mL and 102 ng/mL (Cmax) 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).

Figure 4 - Pharmacokinetic/Pharmacodynamic Response (N=27) to ELIGARD® 45 mg - Patients Dosed Initially and at Month 6

There was no evidence of significant accumulation during repeated dosing. Nondetectable leuprolide plasma concentrations have been occasionally observed during ELIGARD® 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®. 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®.

Special Populations

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

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