Eligard (Leuprolide Acetate) - Description and Clinical Pharmacology

DESCRIPTION

ELIGARD® is a sterile polymeric matrix formulation of leuprolide acetate, a GnRH agonist, for subcutaneous injection.  It is designed to deliver leuprolide acetate at a controlled rate over a one-, three-, four- or six-month therapeutic period.

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH) 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® 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® is administered subcutaneously, where it forms a solid drug delivery depot.

One syringe contains the ATRIGEL® Delivery System and the other contains leuprolide acetate.  ATRIGEL® is a polymeric (non-gelatin containing) delivery system consisting of a biodegradable poly (DL-lactide-co-glycolide) (PLGH or PLG) polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP).

Refer to Table 5 for the delivery system composition and constituted product formulation for each ELIGARD® product.

Table 5.  ELIGARD® Delivery System Composition and Constituted Product Formulatio n

		ELIGARD® 7.5 mg	ELIGARD® 22.5 mg	ELIGARD® 30 mg	ELIGARD® 45 mg
ATRIGEL® Delivery System Syringe	Polymer	PLGH	PLG	PLG	PLG
	Polymer description	Copolymer containing carboxyl endgroups	Copolymer with hexanediol	Copolymer with hexanediol	Copolymer with hexanediol
	Polymer DL-lactide to Glycolide Molar Ratio	50:50	75:25	75:25	85:15
Constituted Product	Polymer delivered	82.5 mg	158.6 mg	211.5 mg	165 mg
	NMP delivered	160.0 mg	193.9 mg	258.5 mg	165 mg
	Leuprolide acetate delivered	7.5 mg	22.5 mg	30 mg	45 mg
	Approximate Leuprolide free base equivalent	7.0 mg	21 mg	28 mg	42 mg
	Approximate administered formulation weight	250 mg	375 mg	500 mg	375 mg
	Approximate injection volume	0.25 mL	0.375 mL	0.5 mL	0.375 mL

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® 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 11).

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 12).

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 13).

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 14).

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 11.  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).

Figure 11. Pharmacokinetic/Pharmacodynamic Response (N=20) to ELIGARD® 7.5 mg – Patients Dosed Initially and at Months 1 and 2

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

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 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® 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 13.  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).

Figure 13. 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 14.  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).

Figure 14. 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.  Non-detectable 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. 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 (M-1) metabolite.

Excretion.  No drug excretion study was conducted with ELIGARD®.

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 Patient s

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® in hepatically and renally impaired patients have not been determined.

NONCLINICAL TOXICOLOGY

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

Two-year carcinogenicity studies were conducted with leuprolide acetate in rats and mice.  In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg).  There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group).  In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. No carcinogenicity studies have been conducted with ELIGARD®.

Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems and with ELIGARD® 7.5 mg in bacterial systems.  These studies provided no evidence of a mutagenic potential.

CLINICAL STUDIES

One open-label, multicenter study was conducted with each ELIGARD® 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® 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® 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® 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® 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® 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)	117 *   (111 † completed)	90 (82 completed ‡)	111 (103 completed §)
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 below castrate threshold (≤50 ng/dL)		Day 28	112 of 119 (94.1%)	115 of 116 (99%)	85 of 89 (96%)	108 of 109 (99.1%)
		Day 35	-	116 (100%)	-	-
		Day 42	119 (100%)	-	89 (100%)	-
		Conclusion	117 ¶   (100%)	111 (100%)	81 (99%)	102 (99%)
*  One patient received less than a full dose at Baseline, never suppressed, and was withdrawn at Day 73 and given an alternate treatment.
†  All non-evaluable patients who attained castration by Day 28 maintained castration at each timepoint up to and including the time of withdrawal.
‡  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.
§  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.
¶  Two patients withdrew for reasons unrelated to drug.

Figure 15.  ELIGARD® 7.5 mg Mean Serum Testosterone Concentrations (n=117)

Figure 16.  ELIGARD® 22.5 mg Mean Serum Testosterone Concentrations (n=111)

Figure 17.  ELIGARD® 30 mg Mean Serum Testosterone Concentrations (n=90)

Figure 18.  ELIGARD® 45 mg Mean Serum Testosterone Concentrations (n=103)

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® in reducing serum PSA values.

Table 8. Effect of ELIGARD® 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 = 0 *	88%	94%	90%	90%
	WHO Status = 1 †	11%	6%	10%	7%
	WHO Status = 2 ‡				3%
	Mean Bone Pain § (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 Prostate Abnormalities	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%)
*  WHO Status = 0 classified as “fully active.”
†  WHO Status = 1 classified as “restricted in strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.”
‡  WHO Status = 2 classified as “ambulatory but unable to carry out work activities.”
§  Pain score scale: 1 (no pain) to 10 (worst pain possible).