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Pharmacology: Pharmacodynamics: Triptorelin is a synthetic decapeptide agonist analog of gonadotropin-releasing hormone (GnRH). After the initial administration, there is a transient increase in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol. However, triptorelin is a potent inhibitor of gonadotropin secretion with chronic and continuous (usually 2 to 4 weeks after initiation of therapy) administration of therapeutic doses, resulting to sustained reduction in LH and FSH secretion and suppression of testicular and ovarian steroidogenesis. A reduction of serum testosterone concentration to a level typically seen in surgically castrated men is obtained. Consequently, tissues and functions that depend on these hormones for maintenance become quiescent. These effects are usually reversible after discontinuation of treatment.
In patients with metastatic castration-resistant prostate cancer, clinical studies have shown the benefit from the addition of abiraterone acetate, an androgen biosynthesis inhibitor, or of enzalutamide, an androgen receptor inhibitor, to GnRH analogues, such as triptorelin.
Pharmacokinetics: Triptorelin is inactive when given orally. Following a single intramuscular (IM) injection to patients with prostate cancer, mean peak triptorelin serum concentrations (Cmax) 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 doses, respectively. Triptorelin did not accumulate over 9 months (3.75 mg and 11.25 mg) and 12 months (22.5 mg) of treatment.
After IM injection of prolonged-release triptorelin 3 mg in patients with endometriosis, the maximum blood level of triptorelin is obtained between 2 to 6 hours after injection and the peak value reached is 11 ng/mL. There was no evidence of accumulation of triptorelin following monthly injections over 6 months. The minimum blood level oscillates between 0.1 and 0.2 ng/mL. The bioavailability of the prolonged-release product is approximately 50%.
Results of pharmacokinetic investigations conducted in healthy men and women indicate that after intravenous (IV) bolus administration, triptorelin is distributed and eliminated according to a three-compartment model, and corresponding half-lives are approximately 6 minutes, 45 minutes and 3 hours in men, and 3 minutes, 47 minutes, and 5 hours in women.
The volume of distribution following a single IV bolus dose of 0.5 mg of triptorelin peptide was 30 to 33 L in healthy male volunteers and women with endometriosis. It is not known whether triptorelin is distributed into milk and there is no evidence that it binds to plasma proteins.
Triptorelin is degraded by peptidases in different tissues and plasma into inactive fragments, or is cleared by the kidneys and liver. It is unlikely that hepatic microsomal enzymes (cytochrome P450) are involved in the metabolism or clearance of triptorelin. The effect of triptorelin on the activity of other drug metabolizing enzymes is also unknown. In vitro studies demonstrated that triptorelin is not a significant CYP inhibitor/inducer, and P-glycoprotein substrate or inhibitor. No metabolites of triptorelin have been identified.
Triptorelin is eliminated by the kidneys and principally by the liver. Following IV administration of 0.5 mg triptorelin peptide to 6 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.
Following a 0.5 mg IV bolus dose in 19 women, the total clearance was estimated to be 110 mL/min. Twenty percent (20%) of the dose was eliminated in the urine.
Special Populations: Pediatric: In children 6 to 8 years old with central precocious puberty, triptorelin reached its Cmax 4 hours after each injection. The geometric mean Cmax after the first and second triptorelin injections are 39.9 ng/mL and 36.5 ng/mL, respectively. There was no significant accumulation detected following the second triptorelin injection, as shown by the mean geometric accumulation ratio of 0.91 for Cmax.
Age and Race: The effects of age and race in the pharmacokinetics of triptorelin have not been studied systematically. However, in a pharmacokinetic study with healthy male volunteers aged 20 to 22 years with elevated creatinine clearance (approximately 150 mL/min), triptorelin was eliminated twice as fast in the young population 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 known to decrease with age.
Hepatic and Renal Impairment: Following the IV administration of 0.5 mg triptorelin peptide, the percentage of the dose excreted in urine as intact peptide was increased in patients with liver disease who have a creatinine clearance of 89.9 mL/min than in healthy volunteers with a creatinine clearance of 149.9 mL/min (62.3% versus 41.7%).
Renal and hepatic impairment did not affect the distribution half-life of 0.5 mg triptorelin administered as an IV bolus injection. However, renal insufficiency led to a decrease in total triptorelin clearance proportional to the decrease in creatinine clearance. Moreover, increases in volume of distribution and subsequent increase in elimination half-life were also observed. Subjects with hepatic insufficiency have a more pronounced decrease in triptorelin clearance than that observed in subjects with renal insufficiency. Since there were only minimal increases in the volume of distribution, the elimination half-life of subjects with hepatic insufficiency was similar to that of patients with renal insufficiency. In males with hepatic or moderate or severe renal impairment, the area under the plasma concentration-time curve (AUC) increased two- to four-fold compared with healthy males.
