Meant to drop this in here a while ago but got sidetracked:
CLINICAL PHARMACOLOGY
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.
Pharmacodynamics
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 (triptorelin pamoate for injectable suspension) :
TRELSTAR (triptorelin pamoate for injectable suspension) 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 (triptorelin pamoate for injectable suspension) 11.25 mg: serum testosterone levels first increased, peaking on Days 2 â?? 3, and declined thereafter to low levels by Weeks 3 â?? 4 in men with advanced prostate cancer.
TRELSTAR (triptorelin pamoate for injectable suspension) 22.5 mg: serum testosterone levels first increased, peaking on Day 3, and declined thereafter to low levels by Weeks 3 â?? 4 in men with advanced prostate cancer.
Pharmacokinetics
Results of pharmacokinetic investigations conducted in healthy men indicate that after intravenous bolus administration, triptorelin is distributed and eliminated according to a 3-compartment model and corresponding half-lives are approximately 6 minutes, 45 minutes, and 3 hours.
Absorption
Following a single intramuscular injection of TRELSTAR (triptorelin pamoate for injectable suspension) 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.
Distribution
The volume of distribution following a single intravenous bolus dose of 0.5 mg of triptorelin peptide was 30 â?? 33 L in healthy male volunteers. There is no evidence that triptorelin, at clinically relevant concentrations, binds to plasma proteins.
Metabolism
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.
Excretion
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.
AND
Triptorelin (Systemic)
VA CLASSIFICATION
Primary: AN500
Commonly used brand name(s): Trelstar Depot.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antineoplastic â??
Indications
Accepted
Carcinoma, prostate (treatment)â??Triptorelin is indicated for the palliative treatment of advanced prostatic carcinoma.{01}
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weightâ??
Triptorelin: 1311. 45{02}
Triptorelin pamoate: 1699.9{01}
Mechanism of action/Effect:
Triptorelin is a synthetic luteinizing hormone releasing hormone (LHRH) analog. Like naturally occurring LHRH that is produced by the hypothalamus, initial or intermittent administration of triptorelin stimulates release of gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the anterior pituitary. Long-term, sustained use of triptorelin is associated with an early phase of increased LH and FSH levels, followed by their suppression.{01}
In males, the release of LH and FSH results in a transient increase in testosterone concentrations. However, monthly administration of triptorelin in the treatment of prostatic carcinoma suppresses secretion of LH and FSH, with a resultant fall in testosterone concentrations and a pharmacologic castration within 4 weeks following initial administration.{01}
Other actions/effects:
A transient surge in circulating estradiol also occurs following initiation of triptorelin therapy, but chronic and continuous administration results in a marked reduction of ovarian steroidogenesis.{01}
Distribution:
Following intravenous administration of 0.5 mg of triptorelin , the apparent volume of distribution was 30â??33 L in healthy male volunteers.{01}
Protein binding:
There is no evidence that triptorelin, at clinically relevant concentrations, binds to plasma proteins{01}.
Biotransformation:
The mechanism by which triptorelin is metabolized is unknown. Hepatic microsomal enzymes (specifically, the P-450 system) is unlikely to be involved, but the activity of other drug-metabolizing enzymes in unknown; 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, rapidly degraded in the plasma, or are cleared by the kidneys.{01}
Half-life:
Following intravenous administration of 0.5 mg of triptorelin peptide :
Males with normal renal function (average creatinine clearance 150 mL per minute [mL/min]): 2.81 hours.{01}
Males with moderate renal function impairment (average creatinine clearance 40 mL/min): 6.56 hours.{01}
Males with severe renal function impairment (average creatinine clearance 9 mL/min): 7.65 hours.{01}
Males with liver function impairment (average creatinine clearance 90 mL/min): 7.58 hours.{01}
Although half-life is increased in patients with liver or renal function impairment, it is unknown whether dosage adjustment is required.{01}
Onset of action:
Transient increases in testosterone occurs within the first 4 days of therapy. A decline in testosterone concentrations to castration levels occurs within 4 weeks.{01}
Time to peak concentration:
1 hour (range, 1 to 3 hours).{01}
Peak plasma concentration:
Mean, 28.43 nanograms per mL following intramuscular administration of 3.75 mg of triptorelin pamoate to healthy male volunteers{01}
Duration of action:
Suppression of testosterone concentrations to castration levels persists for the duration of therapy. Plasma concentrations decreased to 0.84 nanograms/mL at 4 weeks in healthy males that received 3.75 mg of triptorelin pamoate intramuscularly; at 8 weeks following administration, testosterone plasma concentrations had returned to near baseline levels.{01}
Elimination:
Following intravenous administration of 0.5 mg of triptorelin peptide â??
Hepatic: unknown amount.{01}
Renal: 42% as intact peptide; increases to 62% in patients with liver disease and decreased creatinine clearance.{01}
Precautions to Consider
Cross-sensitivity and/or related problems
Patients with a known hypersensitivity to other LHRH agonists or to LHRH may be sensitive to triptorelin.{01}
Carcinogenicity
The incidence of benign and malignant pituitary tumors and histiosarcomas , as well as mortality, increased with dose in rats given 0.3, 2 and 8 times the recommended human therapeutic dose (based on body surface area) over 13-19 months. No oncogenic effect was noted in mice given approximately 8 times the human therapeutic dose (based on body surface area) every 28 days for 18 months.{01}