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Plenaxis (Abarelix) - Description and Clinical Pharmacology



Abarelix for injectable suspension (Plenaxis®) is a synthetic decapeptide with potent antagonistic activity against naturally occurring gonadotropin releasing-hormone (GnRH).

Plenaxis® inhibits gonadotropin and related androgen production by directly and competitively blocking GnRH receptors in the pituitary.

Abarelix is chemically described as acetyl-D-(beta)-naphthylalanyl-D-4-chlorophenylalanyl -D-3-pyridylalanyl-L-seryl-L-N-methyl-tyrosyl-D-asparagyl-L-leucyl-L-N([egr]) -isopropyl-lysyl-L-prolyl-D-alanyl-amide. It is initially manufactured as an acetate water complex and converted to a carboxymethylcellulose (CMC) water complex in manufacturing the drug product. The molecular weight for abarelix anhydrous free base is 1416.06.

The structural formula for abarelix peptide is:

Abarelix for injectable suspension is supplied as a white to off-white sterile dry powder which, when mixed with the diluent, 0.9% Sodium Chloride Injection, USP, becomes a depot suspension intended for intramuscular (IM) injection.

The single-dose vial contains 113 mg of anhydrous free base abarelix peptide (net) supplied in an abarelix CMC complex. This complex also contains 19.1 to 31 mg of CMC. After the vial is reconstituted with 2.2 mL of 0.9% sodium chloride injection, 2 mL is administered to deliver a dose of 100 mg of abarelix (net) as the abarelix CMC complex at a pH of 5±1.



Abarelix exerts its pharmacological action by directly suppressing luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion and thereby reducing the secretion of testosterone by the testes. Due to the direct inhibition of the secretion of LH by abarelix, there is no initial increase in serum testosterone concentrations.

Saturation binding studies revealed that [125 I]-abarelix has a very high affinity (KD= 0.1 nM) for the rat pituitary LHRH receptor.


A single dose (100 mg IM) of Plenaxis® was given to 14 healthy male volunteers 52 to 75 years of age, with body weight of 61.6 to 110.5 kg, and the pharmacokinetic information is provided in Table 1:

Table 1. Mean ± SD Pharmacokinetic Parameter Values of 100 mg of Plenaxis® Following a Single IM Injection (n = 14)
(ng · day/mL)
43.4 ± 32.3 3.0 ± 2.9 500 ± 96 208 ± 48 13.2 ± 3.2


Following IM administration of 100 mg of Plenaxis®, abarelix is absorbed slowly with a mean peak concentration of 43.4 ng/mL observed approximately 3 days after the injection.


The apparent volume of distribution during the terminal phase determined after IM administration of Plenaxis® was 4040 ± 1607 liters, implying that abarelix probably distributes extensively within the body.


In vitro hepatocyte (rat, monkey, human) studies and in vivo studies in rats and monkeys showed that the major metabolites of abarelix were formed via hydrolysis of peptide bonds. No significant oxidative or conjugated metabolites of abarelix were found either in vitro or in vivo. There is no evidence of cytochrome P-450 involvement in the metabolism of abarelix.


In humans, approximately 13% of unchanged abarelix was recovered in urine after a 15 µg/kg IM injection; there were no detectable metabolites in urine. Renal clearance of abarelix was 14.4 L/day (or 10 mL/min) after administration of 100 mg Plenaxis®.


Effects of Plenaxis® on Serum Testosterone: The effectiveness of Plenaxis® in suppressing serum testosterone was studied in two randomized, open-label, active-comparator trials. Patients were not those with advanced symptomatic prostate cancer. They were randomized in a 2:1 ratio to Plenaxis® 100 mg IM versus LHRH agonist (Study 1) or to Plenaxis® versus LHRH agonist + nonsteroidal antiandrogen (Study 2). Plenaxis® was administered IM on Days 1, 15, 29 (Week 4), then every 4 weeks thereafter for at least 6 months (24 weeks). LHRH agonist and nonsteroidal antiandrogen were administered in standard fashion. After completing 6 months of treatment, patients could continue randomized treatment for an additional 6 months.

Avoidance of testosterone surge: In both studies combined, 100% (348/348) of Plenaxis® patients and 16% (28/172) of comparator patients avoided a testosterone surge.

Attainment of medical castration: The percentage of patients who attained serum testosterone concentration

Table 2. Percentage of patients who attained medical castration (serum testosterone concentration
Day Total N % Castrate
2 339 24%
4 333 56%
8 348 70%
15 347 73%
29 347 94%

Attainment and maintenance of medical castration: Successful response was defined as attainment of medical castration on Day 29 and maintenance through Day 85 (where no two consecutive serum testosterone concentrations between Days 29 and 85 were greater than 50 ng/dL). In Study 1, 92% of Plenaxis® patients responded and 96% of LHRH agonist patients responded. In Study 2, 93% of Plenaxis® patients and 95% of LHRH agonist + nonsteroidal antiandrogen patients responded.

However, when failure was defined as any observed serum testosterone > 50 ng/dL (including transient elevations) just prior to dosing on Day 29 and every 28 days thereafter, effectiveness of testosterone suppression decreased over time. Results of this analysis are summarized in Table 3.

Table 3. Percentage of patients who attained and maintained medical castration; [no serum testosterone >50 ng/dL just prior to dosing on Day 29 and every 28 days thereafter]
Day Study 1 N Study 2 N
Plenaxis® Plenaxis®
85 84% 176 92% 164
169 75% 166 87% 155
365 62% 93 71% 86

Effects of Plenaxis® on Cardiac Electrophysiology: In a single, active-controlled, clinical study comparing Plenaxis® to LHRH agonist + nonsteroidal antiandrogen, periodic electrocardiograms were performed. Both therapies prolonged the mean Fridericia-corrected QT interval by >10 msec from baseline. In approximately 20% of patients in both groups, there were either changes from baseline QTc of >30 msec, or end-of-treatment QTc values exceeding 450 msec. Similar results were observed in 2 other Phase 3 studies with Plenaxis® and the active-control treatments. It is unclear whether these changes were directly related to study drugs, to androgen deprivation therapy, or to other variables.



Data from Hispanics, Blacks and Caucasians demonstrated that race appeared to have no influence on the pharmacokinetics of Plenaxis®.


The pharmacokinetics of Plenaxis® in hepatically and/or renally impaired patients have not been determined.


There have been no studies of Plenaxis® in pediatric patients.


One study of Plenaxis® was conducted in 81 men with advanced symptomatic prostate cancer who were at risk for clinical exacerbation ("clinical flare") if treated with an LHRH agonist. The objective of this open-label, multicenter, uncontrolled, single-arm study was to demonstrate that such patients could avoid orchiectomy through at least 12 weeks of treatment. In this trial, treatment was to be given for at least 6 months with the option to continue treatment in an extension trial.

Of the 81 patients who enrolled, 9 patients from one site were excluded from the efficacy analysis due to inadequate documentation by the study investigator. The specific reasons given for enrollment of the 72 patients were: bone pain from prostate cancer skeletal metastases (n = 31); an enlarged prostate gland or pelvic mass causing bladder neck outlet obstruction (n = 25); bilateral retroperitoneal adenopathy with ureteral obstruction (n = 9); impending neurological compromise from spinal, spinal cord, or epidural metastases (n = 6); or other (n = 1). The median age was 73 years, range 40 to 94 years. There were 62 Caucasians, 6 African Americans and 4 Hispanics.

Plenaxis® 100 mg was administered via IM injection on Days 1, 15 and 29, then every 4 weeks thereafter. Twelve patients discontinued prior to Day 169 for the following reasons: adverse event (n=2), voluntary withdrawal (n=3), death (n=4), and "other" (n=3). Sixty patients were treated for at least 24 weeks; in the extension phase, 33 patients for at least 48 weeks and 15 patients for at least 96 weeks. None (0%) of the 72 patients required orchiectomy while being treated with Plenaxis®, including the extension phase (median combined duration of therapy was 40 weeks). However, 2 patients were withdrawn before week 12 for treatment-related adverse events (immediate-onset systemic allergic reactions consisting of urticaria, and urticaria and pruritis, respectively) and received alternate therapy. In this trial, medical castration (defined as serum total testosterone concentration Although the study was not designed to assess specific clinical outcomes, the following were observed:

  • None (0) of 8 patients with vertebral or epidural metastases and without neurological symptoms developed neurological symptoms.
  • Ten of 13 patients with bladder outlet obstruction and a bladder drainage catheter had the catheter removed by 12 weeks.
  • Eleven of 15 patients with pain due to skeletal metastases were able to reduce the potency, dose and/or frequency of narcotic analgesia at 12 weeks.

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