Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other hormone antagonists and related agents, ATC code: L02BX02 
Mechanism of action.
Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone (T) by the testes. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that removes the source of androgen. Unlike GnRH agonists, GnRH antagonists do not induce a LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic flare after the initiation of treatment.

A single dose of 240 mg degarelix, followed by a monthly maintenance dose of 80 mg, rapidly causes a decrease in the concentrations of LH, FSH and subsequently testosterone. The plasma concentration of dihydrotestosterone (DHT) decreases in a similar manner to testosterone.

Degarelix is effective in achieving and maintaining testosterone suppression well below medical castration level of 0.5 ng/ml. Maintenance monthly dosing of 80 mg resulted in sustained testosterone suppression in 97% of patients for at least one year. No testosterone microsurges were observed after re-injection during degarelix treatment. Median testosterone levels after one year of treatment were 0.087 ng/ml (interquartile range 0.06-0.15) N=167.

Results of the confirmatory Phase III study
The efficacy and safety of degarelix was evaluated in an open-label, multi-centre, randomised, active comparator controlled, parallel-group study. The study investigated the efficacy and safety of two different degarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/ml) followed by monthly doses subcutaneous administration of 160 mg (40 mg/ml) or 80 mg (20 mg/ml), in comparison to monthly intramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. In total 620 patients were randomised to one of the three treatment groups, of which 504 (81%) patients completed the study. In the degarelix 240/80 mg treatment group 41 (20%) patients discontinued the study, as compared to 32 (16%) patients in the leuprorelin group.

Of the 610 patients treated
•     31% had localised prostate cancer
•     29% had locally advanced prostate cancer
•     20% had metastatic prostate cancer
•     7% had an unknown metastatic status
•     13% had previous curative intent surgery or radiation and a rising PSA 
Baseline demographics were similar between the arms. The median age was 74 years (range 47 to 98 years). The primary objective was to demonstrate that degarelix is effective with respect to achieving and maintaining testosterone suppression to below 0.5 ng/ml, during 12 months of treatment.
The lowest effective maintenance dose of 80 mg degarelix was chosen.

Attainment of serum testosterone (T) ≤0.5 ng/ml
FIRMAGON is effective in achieving fast testosterone suppression, see Table 2.

Table 2: Percentage of patients attaining T≤0.5 ng/ml after start of treatment.
Time                         Degarelix 240/80 mg                  Leuprorelin 7.5 mg Day 1                        52%                                  0%
Day 3                        96%                                  0%
Day 7                        99%                                  1%
Day 14                       100%                                 18% Day 28                       100%                                 100% 
Avoidance of testosterone surge
Surge was defined as testosterone exceeding baseline by ≥15% within the first 2 weeks.
None of the degarelix-treated patients experienced a testosterone surge; there was an average decrease of 94% in testosterone at day 3. Most of the leuprorelin-treated patients experienced testosterone surge; there was an average increase of 65% in testosterone at day 3. This difference was statistically significant (p<0.001).

Figure 1: Percentage change in testosterone from baseline by treatment group until day 28 (median with interquartile ranges).



The primary end-point in the study was testosterone suppression rates after one year of treatment with degarelix or leuprorelin. The clinical benefit for degarelix compared to leuprorelin plus anti-androgen in the initial phase of treatment has not been demonstrated.


Testosterone Reversibility
In a study involving patients with rising PSA after localised therapy (mainly radical prostatectomy and radiation) were administered FIRMAGON for seven months followed by a seven months monitoring period. The median time to testosterone recovery (>0.5 ng/mL, above castrate level) after discontinuation of treatment was 112 days (counted from start of monitoring period, i.e 28 days after last injection). The median time to testosterone >1.5 ng/mL (above lower limit of normal range) was 168 days.


Long-term effect
Successful response in the study was defined as attainment of medical castration at day 28 and maintenance through day 364 where no single testosterone concentration was greater than 0.5 ng/ml.

Table 3: Cumulative probability of testosterone ≤0.5 ng/ml from Day 28 to Day 364.
Degarelix 240/80 mg          Leuprorelin 7.5 mg
N=207                        N=201
No. of responders                     202                          194 Response Rate                        97.2%                         96.4% (confidence intervals)*              (93.5; 98.8%)                 (92.5; 98.2%) * Kaplan Meier estimates within group

Attainment of prostate specific antigen (PSA) reduction
Tumour size was not measured directly during the clinical trial programme, but there was an indirect beneficial tumour response as shown by a 95% reduction after 12 months in median PSA for degarelix.

The median PSA in the study at baseline was:
•    for the degarelix 240/80 mg treatment group 19.8 ng/ml (interquartile range: P25 9.4 ng/ml, P75 46.4 ng/ml)
•    for the leuprorelin 7.5 mg treatment group 17.4 ng/ml (interquartile range: P25 8.4 ng/ml, P75 56.5 ng/ml)

Figure 2: Percentage change in PSA from baseline by treatment group until day 56 (median with interquartile ranges).



This difference was statistically significant (p<0.001) for the pre-specified analysis at day 14 and day 28.

Prostate specific antigen (PSA) levels are lowered by 64% two weeks after administration of degarelix, 85% after one month, 95% after three months, and remained suppressed (approximately 97%) throughout the one year of treatment.
From day 56 to day 364 there were no significant differences between degarelix and the comparator in the percentage change from baseline.

Effect on prostate volume
Three months therapy with degarelix (240/80 mg dose regimen) resulted in a 37% reduction in prostate volume as measured by trans-rectal ultrasound scan (TRUS) in patients requiring hormonal therapy prior to radiotherapy and in patients who were candidates for medical castration. The prostate volume reduction was similar to that attained with goserelin plus anti-androgen protection.

Effect on QT/QTc intervals
In the confirmatory study comparing FIRMAGON to leuprorelin periodic electrocardiograms were performed. Both therapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of the patients. From baseline to end of study the median change for FIRMAGON was 12.0 msec and for leuprorelin it was 16.7 msec.

Anti-degarelix antibodies
Anti-degarelix antibody development has been observed in 10% of patients after treatment with FIRMAGON for one year and 29% of patients after treatment with FIRMAGON for up to 5.5 years .
There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation after. up to 5.5 years of treatment.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with FIRMAGON in all subsets of the paediatric population (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
Following subcutaneous administration of 240 mg degarelix at a concentration of 40 mg/ml to prostate cancer patients in the pivotal study CS21, AUC0-28 days was 635 (602-668) day*ng/ml, Cmax was 66.0 (61.0-71.0) ng/ml and occurred at tmax at 40 (37-42) hours. Mean trough values were approximately 11-12 ng/ml after the starting dose and 11-16 ng/ml after maintenance dosing of 80 mg at a concentration of 20 mg/ml. Cmax degarelix plasma concentration decreases in a biphasic fashion, with a mean terminal half-life (t½) of 29 days for the maintenance dose. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from the depot formed at the injection site(s). The pharmacokinetic behavior of the medicinal product is influenced by its concentration in the solution for injection. Thus, Cmax and bioavailability tend to decrease with increasing dose concentration while the half-life is increased. Therefore, no other dose concentrations than the recommended should be used.

Distribution
The distribution volume in healthy elderly men is approximately 1 l/kg. Plasma protein binding is estimated to be approximately 90%.

Biotransformation
Degarelix is subject to common peptidic degradation during the passage of the hepato-biliary system and is mainly excreted as peptide fragments in the faeces. No significant metabolites were detected in 
plasma samples after subcutaneous administration. In vitro studies have shown that degarelix is not a substrate for the human CYP450 system.

Elimination
In healthy men, approximately 20-30% of a single intravenously administered dose is excreted in the urine, suggesting that 70-80% is excreted via the hepato-biliary system. The clearance of degarelix when administered as single intravenous doses (0.864-49.4 µg/kg) in healthy elderly men was found to be 35-50 ml/h/kg.

Special populations:
Patients with renal impairment
No pharmacokinetic studies in renally impaired patients have been conducted. Only about 20-30% of a given dose of degarelix is excreted unchanged by the kidneys. A population pharmacokinetics analysis of the data from the confirmatory Phase III study has demonstrated that the clearance of degarelix in patients with mild to moderate renal impairment is reduced by approximately 23%; therefore, dose adjustment in patients with mild or moderate renal impairment is not recommended. Data on patients with severe renal impairment is scarce and caution is therefore warranted in this patient population.

Patients with hepatic impairment
Degarelix has been investigated in a pharmacokinetic study in patients with mild to moderate hepatic impairment. No signs of increased exposure in the hepatically impaired subjects were observed compared to healthy subjects. Dose adjustment is not necessary in patients with mild or moderate hepatic impairment. Patients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group.