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Mechanism of Action
Triptorelin is a synthetic decapeptide agonist analog of gonadotropin releasing hormone (GnRH). Comparative in vitro studies showed that triptorelin was 100-fold more active than native GnRH in stimulating luteinizing hormone release from monolayers of dispersed rat pituitary cells in culture and 20-fold more active than native GnRH in displacing 125I-GnRH from pituitary receptor sites. In animal studies, triptorelin pamoate was found to have 13-fold higher luteinizing hormone-releasing activity and 21-fold higher follicle-stimulating hormone-releasing activity compared to the native GnRH.
Following the first administration, there is a transient surge in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol [see ADVERSE REACTIONS]. After chronic and continuous administration, usually 2 to 4 weeks after initiation of therapy, a sustained decrease in LH and FSH secretion and marked reduction of testicular steroidogenesis are observed. A reduction of serum testosterone concentration to a level typically seen in surgically castrated men is obtained. Consequently, the result is that tissues and functions that depend on these hormones for maintenance become quiescent. These effects are usually reversible after cessation of therapy.
Following a single intramuscular injection of TRELSTAR:
TRELSTAR 3.75 mg: serum testosterone levels first increased, peaking on Day 4, and declined thereafter to low levels by Week 4 in healthy male volunteers.
TRELSTAR 11.25 mg: serum testosterone levels first increased, peaking on Days 2 – 3, and declined thereafter to low levels by Weeks 3 – 4 in men with advanced prostate cancer.
TRELSTAR 22.5 mg: serum testosterone levels first increased, peaking on Day 3, and declined thereafter to low levels by Weeks 3 – 4 in men with advanced prostate cancer.
Results of pharmacokinetic investigations conducted in healthy men indicate that after intravenous bolus administration, triptorelin is distributed and eliminated according to a 3compartment model and corresponding half-lives are approximately 6 minutes, 45 minutes, and 3 hours.
Following a single intramuscular injection of TRELSTAR to patients with prostate cancer, mean peak serum concentrations of 28.4 ng/mL, 38.5 ng/mL, and 44.1 ng/mL occurred in 1 to 3 hours after the 3.75 mg, 11.25 mg, and 22.5 mg formulations, respectively.
Triptorelin did not accumulate over 9 months (3.75 mg and 11.25 mg) or 12 months (22.5 mg) of treatment.
The volume of distribution following a single intravenous bolus dose of 0.5 mg of triptorelin peptide was 30 – 33 L in healthy male volunteers. There is no evidence that triptorelin, at clinically relevant concentrations, binds to plasma proteins.
The metabolism of triptorelin in humans is unknown, but is unlikely to involve hepatic microsomal enzymes (cytochrome P-450). The effect of triptorelin on the activity of other drug metabolizing enzymes is also unknown. Thus far, no metabolites of triptorelin have been identified. Pharmacokinetic data suggest that C-terminal fragments produced by tissue degradation are either completely degraded in the tissues, or rapidly degraded in plasma, or cleared by the kidneys.
Triptorelin is eliminated by both the liver and the kidneys. Following intravenous administration of 0.5 mg triptorelin peptide to six healthy male volunteers with a creatinine clearance of 149.9 mL/min, 41.7% of the dose was excreted in urine as intact peptide with a total triptorelin clearance of 211.9 mL/min. This percentage increased to 62.3% in patients with liver disease who have a lower creatinine clearance (89.9 mL/min). It has also been observed that the nonrenal clearance of triptorelin (patient anuric, CIcreat = 0) was 76.2 mL/min, thus indicating that the nonrenal elimination of triptorelin is mainly dependent on the liver.
Age and Race
The effects of age and race on triptorelin pharmacokinetics have not been systematically studied. However, pharmacokinetic data obtained in young healthy male volunteers aged 20 to 22 years with an elevated creatinine clearance (approximately 150 mL/min) indicate that triptorelin was eliminated twice as fast in this young population as compared with patients with moderate renal insufficiency. This is related to the fact that triptorelin clearance is partly correlated to total creatinine clearance, which is well known to decrease with age [see Use in Specific Populations].
TRELSTAR has not been evaluated in patients less than 18 years of age [see Use In Specific Populations].
Hepatic and Renal Impairment
After an intravenous bolus injection of 0.5 mg triptorelin, the two distribution half-lives were unaffected by renal and hepatic impairment. However, renal insufficiency led to a decrease in total triptorelin clearance proportional to the decrease in creatinine clearance as well as increases in volume of distribution and consequently, an increase in elimination half-life (see Table 6). In subjects with hepatic insufficiency, a decrease in triptorelin clearance was more pronounced than that observed with renal insufficiency. Due to minimal increases in the volume of distribution, the elimination half-life in subjects with hepatic insufficiency was similar to subjects with renal insufficiency. Subjects with renal or hepatic impairment had 2- to 4-fold higher exposure (AUC values) than young healthy males [see Use In Specific Populations].
Table 6: Pharmacokinetic Parameters (Mean ± SD) in
Healthy Volunteers and Special Populations Following an IV Bolus Injection of
0.5 mg Triptorelin
|Group||Cmax (ng/mL)||AUCinf (h•ng/mL)||Clp (mL/min)||Clrenal (mL/min)||t½ (h)||Clcreat (mL/min)|
|6 healthy male volunteers||48.2 ± 11.8||36.1 ± 5.8||211.9 ± 31.6||90.6 ± 35.3||2.81 ± 1.21||149.9 ± 7.3|
|6 males with moderate renal impairment||45.6 ± 20.5||69.9 ± 24.6||120.0 ± 45.0||23.3 ± 17.6||6.56 ± 1.25||39.7 ± 22.5|
|6 males with severe renal impairment||46.5 ± 14.0||88.0 ± 18.4||88.6 ± 19.7||4.3 ± 2.9||7.65 ± 1.25||8.9 ± 6.0|
|6 males with liver disease||54.1 ± 5.3||131.9 ± 18.1||57.8 ± 8.0||35.9 ± 5.0||7.58 ± 1.17||89.9 ± 15.1|
TRELSTAR 3.75 mg
TRELSTAR 3.75 mg was studied in a randomized, active control trial of 277 men with advanced prostate cancer. The clinical trial population consisted of 59.9% Caucasian, 39.3% Black, and 0.8% Other. There was no difference observed with triptorelin response between racial groups. Men were between 47 and 89 years of age (mean = 71 years). Patients received either TRELSTAR 3.75 mg (N = 140) or an approved GnRH agonist monthly for 9 months. The primary efficacy endpoints were both achievement of castration by Day 29 and maintenance of castration from Day 57 through Day 253.
Castration levels of serum testosterone ( ≤ 1.735 nmol/L; equivalent to 50 ng/dL) in patients treated with TRELSTAR 3.75 mg were achieved at Day 29 in 125 of 137 (91.2%) patients and at Day 57 in 97.7% of patients. Maintenance of castration levels of serum testosterone from Day 57 through Day 253 was found in 96.2% of patients treated with TRELSTAR 3.75 mg.
The presence of an acute-on-chronic flare phenomenon was also studied as a secondary efficacy endpoint. Serum LH levels were measured at 2 hours after repeat TRELSTAR 3.75 mg administration on Days 85 and 169. One hundred twenty-four of the 126 evaluable patients (98.4%) on Day 85 had a serum LH level of ≤ 1.0 IU/L at 2 hours after dosing, indicating desensitization of the pituitary gonadotroph receptors.
TRELSTAR 11.25 mg
TRELSTAR 11.25 mg was studied in a randomized, active control trial of 346 men with advanced prostate cancer. The clinical trial population consisted of 48% Caucasian, 38% Black, and 15% Other. There was no difference observed with triptorelin response between racial groups. Men were between 45 and 96 years of age (mean = 71 years). Patients received either TRELSTAR 11.25 mg (N = 174) every 12 weeks for a total of up to 3 doses (maximum treatment period of 253 days) or TRELSTAR 3.75 mg (N = 172) every 28 days for a total of up to 9 doses. The primary efficacy endpoints were both achievement of castration by Day 29 and maintenance of castration from Day 57 through Day 253.
Castration levels of serum testosterone ( ≤ 1.735 nmol/L; equivalent to 50 ng/dL) were achieved at Day 29 in 167 of 171 (97.7%) patients treated with TRELSTAR 11.25 mg, and maintenance of castration levels of serum testosterone from Day 57 through Day 253 was found in 94.4% of patients treated with TRELSTAR 11.25 mg.
TRELSTAR 22.5 mg
TRELSTAR 22.5 mg was studied in a non-comparative trial of 120 men with advanced prostate cancer. The clinical trial population consisted of 64% Caucasian, 23% Black, and 13% Other, with a mean age of 71.1 years (range 51-93). Patients received TRELSTAR 22.5 mg (N = 120) every 24 weeks for a total of 2 doses (maximum treatment period of 337 days). The primary efficacy endpoints included achievement of castration by Day 29 and maintenance of castration from Day 57 through Day 337.
Castration levels of serum testosterone ( ≤ 1.735 nmol/L; equivalent to 50 ng/dL) were achieved at Day 29 in 97.5% (117 of 120) of patients treated with TRELSTAR 22.5 mg. Castration was maintained in 93.3% of patients in the period from Day 57 to Day 337.
A summary of the clinical studies for TRELSTAR is provided in Table 7.
Table 7: Summary of TRELSTAR Clinical Studies
|Product Strength||3.75 mg||11.25 mg||22.5 mg|
|Number of Patients||137||171||120|
|Treatment Schedule||every 4 weeks||every 12 weeks||every 24 weeks|
|Duration of Study||253 days||253 days||337 days|
|Castration Ratea on Day 29, % (n/N)||91.2% (125/137)||97.7% (167/171)||97.5% (117/120)|
|Rate of Castration Maintenanceb from Days 57 – 253, %||96.2%||94.4%||not applicable|
|Rate of Castration Maintenance from Days 57 – 337, % (n/N)||not applicable||not applicable||93.3% (112/120)c|
|a Maintenance of castration was
calculated using a frequency distribution.
b Cumulative maintenance of castration was calculated using a survival analysis (Kaplan-Meier) technique.
c Calculation includes 5 patients who discontinued the study but who had castrate levels of testosterone prior to discontinuation.
Last reviewed on RxList: 6/28/2011
This monograph has been modified to include the generic and brand name in many instances.
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