Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group:
Hormones and related agents, gonadotropin releasing hormone analogues.
ATC code: L02AE04
Mechanism of action and pharmacodynamic effects
Triptorelin, a GnRH agonist, acts as a potent inhibitor of gonadotrophin secretion when given continuously and in therapeutic doses. In males, animal and human studies show that after administration of triptorelin there is an initial and transient increase in circulating levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone.
However, chronic and continuous administration of triptorelin results in decreased LH and FSH secretion and suppression of testicular and ovarian steroidogenesis. A reduction of serum testosterone levels into the range normally seen in surgically castrated men occurs approximately2 to 4 weeks after initiation of therapy. This results in accessory sexual organ atrophy. These effects are generally reversible upon discontinuation of the medicinal product. In animals, administration of triptorelin resulted in the inhibition of growth of some hormone-sensitive prostate tumours in experimental models.
Clinical efficacy and safety
Administration of Decapeptyl depot 11.25 mg to patients with advanced prostate cancer as an intramuscular injection for a total of 3 doses (9 months) resulted in both achievement of castration levels of testosterone in 97.6% and 92.5% of patients receiving 3-month and 1-month formulations respectively, after four weeks and maintenance of castration levels of testosterone from month 2 through month 9 of treatment.

Pharmacokinetic Properties

5.2.    Pharmacokinetic properties
Absorption:
Following the administration of a single IM injection of Decapeptyl Depot 11.25mg to patients with prostate cancer, the mean tmax was 2 (2-6) hours and Cmax was 37.1 (22.4-57.4) ng/ml.
Triptorelin did not accumulate over 9 months of treatment.

Distribution:
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.
The volume of distribution at steady state of triptorelin following intravenous administration of 0.5 mg triptorelin acetate is approximately 30 l in healthy male volunteers Since there is no evidence that triptorelin at clinically relevant concentrations binds to plasma proteins, medicinalproduct interactions involving binding-site displacement are unlikely.
Biotransformation:
Metabolites of triptorelin have not been determined in humans. However, human pharmacokinetic data show that C-terminal fragments produced by tissue destruction are either completely degraded within tissues or are rapidly and completely degraded in plasma or cleared by the kidneys.
Elimination:
Triptorelin is eliminated by both the liver and kidneys. Following intravenous injection of 0.5 mg triptorelin, 42 % of the dose was excreted in urine as intact triptorelin.
which increased to 62 % in subjects with hepatic impairment. Since creatinine clearance (Clcreat) in healthy volunteers was 150 ml/min and only 90 ml/min in subjects with hepatic impairment, this indicates that the liver is a major site of triptorelin elimination. In these healthy volunteers, the true terminal half-life of triptorelin was 2.8 hours and total clearance of triptorelin 212 ml/min, the latter being dependent on a combination of hepatic and renalelimination.
Other special populations:
Following intravenous administration of 0.5 mg triptorelin to subjects with moderate renal insufficiency (Clcreat 40 ml/min), triptorelin had an elimination half-life of 6.7 hours, 7.81 hours in subjects with severe renal insufficiency (Clcreat 8.9 ml/min) and 7.65 hours in patients with impaired hepatic function (Clcreat 89.9 ml/min).
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) indicated that triptorelin was eliminated twice as fast in the young population. This is related to the fact that triptorelin clearance is correlated to total creatinine clearance, which is well known to decrease with age.
Because of the large safety margin of triptorelin and since Decapeptyl depot 11.25 mg is a sustained release formulation, no dose adjustment is recommended in patients with renal or hepatic impairment.
Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetics/pharmacodynamics relationship of triptorelin is not straightforward to assess, since it is non-linear and time-dependent. Thus, after acute administration in naive subjects, triptorelin induces a dose-dependent increase of LH and FSH responses.
When administered as a sustained release formulation, triptorelin stimulates LH and FSH secretion during the first days post dosing and, in consequence, testosterone secretion. As shown by the results of the different bioequivalence studies, the maximal increase in testosterone is reached after around 4 days with an equivalent Cmax which is independent from the release rate of triptorelin. This initial response is not maintained despite continuous exposure to triptorelin and is followed by a progressive and equivalent decrease of testosterone levels. In this case too, the extent of triptorelin exposure can vary markedly without affecting the overall effect on testosterone serum levels.