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Eligard

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Eligard

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

Continued monthly treatment with ELIGARD (leuprolide acetate) ® 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 11).

One patient received less than a full dose of ELIGARD (leuprolide acetate) ® 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 12).

One patient withdrew from the ELIGARD (leuprolide acetate) ® 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 13).

One patient at Day 1 and another patient at Day 29 were withdrawn from the ELIGARD (leuprolide acetate) ® 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 14).

Leuprolide acetate is not active when given orally.

Pharmacokinetics

Absorption

ELIGARD (leuprolide acetate) ® 7.5 mg

The pharmacokinetics/pharmacodynamics observed during three once-monthly injections in 20 patients with advanced prostate cancer is shown in Figure 11. 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 11: Pharmacokinetic/Pharmacodynamic Response (N=20) to ELIGARD (leuprolide acetate) ® 7.5 mg – Patients Dosed Initially and at Months 1 and 2

Pharmacokinetic/Pharmacodynamic Response - Illustration

A reduced number of sampling timepoints resulted in the apparent decrease in Cmax values with the second and third doses of ELIGARD (leuprolide acetate) ® 7.5 mg (Figure 11).

ELIGARD (leuprolide acetate) ® 22.5 mg

The pharmacokinetics/pharmacodynamics observed during two injections every three months (ELIGARD (leuprolide acetate) ® 22.5 mg) in 22 patients with advanced prostate cancer is shown in Figure 12. 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 12: Pharmacokinetic/Pharmacodynamic Response (N=22) to ELIGARD (leuprolide acetate) ® 22.5 mg – Patients Dosed Initially and at Month 3

Pharmacokinetic/Pharmacodynamic Response (N=22) to ELIGARD® 22.5 mg - Illustration

ELIGARD (leuprolide acetate) ® 30 mg

The pharmacokinetics/pharmacodynamics observed during injections administered initially and at four months (ELIGARD (leuprolide acetate) ® 30 mg ) in 24 patients with advanced prostate cancer is shown in Figure 13. 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 13: Pharmacokinetic/Pharmacodynamic Response (N=24) to ELIGARD (leuprolide acetate) ® 30 mg – Patients Dosed Initially and at Month 4

Pharmacokinetic/Pharmacodynamic Response (N=24) to ELIGARD® 30 mg - Illustration

ELIGARD (leuprolide acetate) ® 45 mg

The pharmacokinetics/pharmacodynamics observed during injections administered initially and at six months (ELIGARD (leuprolide acetate) ® 45 mg) in 27 patients with advanced prostate cancer is shown in Figure 14. Mean serum leuprolide concentrations rose to 82 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 14: Pharmacokinetic/Pharmacodynamic Response (N=27) to ELIGARD (leuprolide acetate) ® 45 mg - Patients Dosed Initially and at Month 6

Pharmacokinetic/Pharmacodynamic Response (N=27) to ELIGARD® 45 mg - Illustration

There was no evidence of significant accumulation during repeated dosing. Non-detectable leuprolide plasma concentrations have been occasionally observed during ELIGARD (leuprolide acetate) ® 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. 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.

No drug metabolism study was conducted with ELIGARD®. Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M1) metabolite.

Excretion

No drug excretion study was conducted with ELIGARD (leuprolide acetate) ®.

Geriatrics

[see Use In Special Populations]

Race

In patients studied, mean serum leuprolide concentrations were similar regardless of race. Refer to Table 6 for distribution of study patients by race.

Table 6: Race Characterization of Study Patients

Race ELIGARD® 7.5 mg ELIGARD® 22.5 mg ELIGARD® 30 mg ELIGARD® 45 mg
White 26 19 18 17
Black - 4 4 7
Hispanic 2 2 2 3

Renal and Hepatic Insufficiency

The pharmacokinetics of ELIGARD (leuprolide acetate) ® in hepatically and renally impaired patients have not been determined.

Clinical Studies

One open-label, multicenter study was conducted with each ELIGARD (leuprolide acetate) ® formulation (7.5 mg, 22.5 mg, 30 mg, and 45 mg) in patients with Jewett stage A though D prostate cancer who were treated with at least a single injection of study drug (Table 7). These studies evaluated the achievement and maintenance of castrate serum testosterone suppression over the duration of therapy (Figures 15-18).

During the AGL9904 study using ELIGARD (leuprolide acetate) ® 7.5 mg, once testosterone suppression was achieved, no patients (0%) demonstrated breakthrough (concentration > 50 ng/dL) at any time in the study.

During the AGL9909 study using ELIGARD (leuprolide acetate) ® 22.5 mg, once testosterone suppression was achieved, only one patient ( < 1%) demonstrated breakthrough following the initial injection; that patient remained below the castrate threshold following the second injection.

During the AGL0001 study using ELIGARD (leuprolide acetate) ® 30 mg, once testosterone suppression was achieved, three patients (3%) demonstrated breakthrough. In the first of these patients, a single serum testosterone concentration of 53 ng/dL was reported on the day after the second injection. In this patient, castrate suppression was reported for all other timepoints. In the second patient, a serum testosterone concentration of 66 ng/dL was reported immediately prior to the second injection. This rose to a maximum concentration of 147 ng/dL on the second day after the second injection. In this patient, castrate suppression was again reached on the seventh day after the second injection and was maintained thereafter. In the final patient, serum testosterone concentrations > 50 ng/dL were reported at 2 and at 8 hours after the second injection. Serum testosterone concentration rose to a maximum of 110 ng/dL on the third day after the second injection. In this patient, castrate suppression was again reached eighteen days after the second injection and was maintained until the final day of the study, when a single serum testosterone concentration of 55 ng/dL was reported.

During the AGL0205 study using ELIGARD (leuprolide acetate) ® 45 mg, once testosterone suppression was achieved, one patient ( < 1%) demonstrated breakthrough. This patient reached castrate suppression at Day 21 and remained suppressed until Day 308 when his testosterone level rose to 112 ng/dL. At Month 12 (Day 336), his testosterone was 210 ng/dL.

Table 7: Summary of ELIGARD (leuprolide acetate) ® Clinical Studies

    7.5 mg 22.5 mg 30 mg 45 mg
Study number   AGL9904 AGL9909 AGL0001 AGL0205
Total Number of patients   120 (117 completed) 1172 (111 completed3) 90 (82 completed4) 111 (103 completed5)
Jewett Stages Stage A - 2 2 5
Stage B - 19 38 43
Stage C 89 60 16 19
Stage D 31 36 34 44
Treatment   6 monthly injections 1 injection (4 patients) 1 injection (5 patients) 1 injection (5 patients)
      2 injections, one every three months (113 patients) 2 injections, one every four months (85 patients) 2 injections, one every six months (106 patients)
Duration of therapy 6 months 6 months 8 months 12 months
Mean testosterone concentration (ng/dL) Baseline 361.3 367.1 385.5 367.7
Day 2 574.6 (Day 3) 588.0 610.0 588.6
Day 14 Below Baseline (Day 10) Below Baseline Below Baseline Below Baseline
Day 28 21.8 27.7 (Day 21) 17.2 16.7
Conclusion 6.1 10.1 12.4 12.6
Number of patients castrate threshold ( ≤ 50 ng/dL) Day 28 112 of 119 115 of 116 85 of 89 (96%) 108 of 109
below (94.1%) (99%)   (99.1%)
Day 35 - 116 (100%) -
Day 42 119 (100%) - 89 (100%) -
Conclusion 1171 (100%) 111 (100%) 81 (99%) 102 (99%)
1 Two patients withdrew for reasons unrelated to drug.
2 One patient received less than a full dose at Baseline, never suppressed, and was withdrawn at Day 73 and given an alternate treatment.
3 All non-evaluable patients who attained castration by Day 28 maintained castration at each timepoint up to and including the time of withdrawal.
4 One patient withdrew on Day 14. All 7 non-evaluable patients who had achieved castration by Day 28 maintained castration at each timepoint, up to and including the time of withdrawal.
5 Two patients were withdrawn prior to the Month 1 blood draw. One patient did not achieve castration and was withdrawn on Day 85. All 5 non-evaluable patients who attained castration by Day 28, maintained castration at each timepoint up to and including the time of withdrawal.

Figure 15: ELIGARD (leuprolide acetate) ® 7.5 mg Mean Serum Testosterone Concentrations (n=117)

ELIGARD® 7.5 mg Mean Serum Testosterone Concentrations - Illustration

Figure 16: ELIGARD (leuprolide acetate) ® 22.5 mg Mean Serum Testosterone Concentrations (n=111)

ELIGARD® 22.5 mg Mean Serum Testosterone Concentrations -  Illustration

Figure 17: ELIGARD (leuprolide acetate) ® 30 mg Mean Serum Testosterone Concentrations (n=90)

ELIGARD® 30 mg Mean Serum Testosterone Concentrations - Illustration

Figure 18: ELIGARD (leuprolide acetate) ® 45 mg Mean Serum Testosterone Concentrations (n=103)

ELIGARD® 45 mg Mean Serum Testosterone Concentrations - Illustration

Serum PSA decreased in all patients in all studies whose Baseline values were elevated above the normal limit. Refer to Table 8 for a summary of the effectiveness of ELIGARD (leuprolide acetate) ® in reducing serum PSA values.

Table 8: Effect of ELIGARD (leuprolide acetate) ® on Patient Serum PSA Values

ELIGARD® 7.5 mg 22.5 mg 30 mg 45 mg
Mean PSA Reduction at Study Conclusion 94% 98% 86% 97%
Patients with Normal PSA at Study Conclusion* 94% 91% 93% 95%
*Among 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. Refer to Table 9 for a summary of these endpoints.

Table 9: Secondary Efficacy Endpoints

    ELIGARD® 7.5 mg ELIGARD® 22.5 mg ELIGARD® 30 mg ELIGARD® 45 mg
Baseline WHO Status = 01 88% 94% 90% 90%
  WHO Status = 12 11% 6% 10% 7%
WHO Status = 23       3%
Mean Bone Pain4(range) 1.22 (1-9) 1.20 (1-9) 1.20 (1-7) 1.38 (1-7)
Mean Urinary Pain (range) 1.12 (1-5) 1.02 (1-2) 1.01 (1-2) 1.22 (1-8)
Mean Urinary Signs and Symptoms (range) Low 1.09 (1-4) Low Low
Number of Patients with ProstateAbnormalities 102 (85%) 96 (82%) 66 (73%) 89 (80%)
    Month 6 Month 6 Month 8 Month 12
Follow-up WHO Status = 0 Unchanged 96% 87% 94%
WHO Status = 1 Unchanged 4% 12% 5%
WHO Status = 2     1% 1%
Mean Bone Pain (range) 1.26 (1-7) 1.22 (1-5) 1.19 (1-8) 1.31 (1-8)
Mean Urinary Pain (range) 1.07 (1-8) 1.10 (1-8) 1.00 (1-1) 1.07 (1-5)
Mean Urinary Signs and Symptoms (range) Modestly Decreased 1.18 (1-7) Modestly Decreased Modestly Decreased
Number of Patients with Prostate Abnormalities 77 (64%) 76 (65%) 54 (60%) 60 (58%)
1 WHO Status = 0 classified as “fully active.”
2 WHO Status = 1 classified as “restricted in strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.”
3 WHO Status = 2 classified as “ambulatory but unable to carry out work activities.”
4 Pain score scale: 1 (no pain) to 10 (worst pain possible).

Last reviewed on RxList: 3/3/2011
This monograph has been modified to include the generic and brand name in many instances.

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