Trelstar Pharmacology, Pharmacokinetics, Studies, Metabolism - Triptorelin pamoate

Trelstar Pharmacology, Pharmacokinetics, Studies, Metabolism - Triptorelin pamoate

CLINICAL PHARMACOLOGY

Triptorelin is a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. 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 brand of triptorelin pamoate for injectable suspension

continuous administration, usually 2 to 4 weeks after initiation of therapy, a sustained decrease in LH and FSH secretion and marked reduction of testicular and ovarian steroidogenesis is observed. In men, 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 (IM) injection of TRELSTAR^TM DEPOT to healthy male volunteers, serum testosterone levels first increased, peaking on day 4, and declined thereafter to low levels by week 4. Similar testosterone profiles were observed in patients with advanced prostate cancer, when injected with TRELSTAR^TM DEPOT. In healthy volunteers, testosterone serum levels returned to near baseline by week 8.

Results of pharmacokinetic investigations conducted in healthy men indicate that after intravenous (IV) bolus administration, trip-torelin is distributed and eliminated according to a 3-compartment model and corresponding half-lives are approximately 6 minutes, 45 minutes, and 3 hours.

Absorption: Triptorelin pamoate is not active when given orally. Intramuscular injection of the depot formulation provides plasma concentrations of triptorelin over a period of 1 month. The pharmacokinetic parameters following a single IM injection of 3.75 mg of TRELSTAR^TM DEPOT to 20 healthy male volunteers are listed in Table 1. The plasma concentrations declined to 0.084 ng/mL at 4 weeks.

¹ Mean ±SD

² Median (range)

³ Computed as the mean AUC of the study divided by the mean AUC of healthy volunteers corrected for dose where AUC=36.1 h·ng/mL and 500 µg IV bolus dose of triptorelin was administered.

Distribution: The volume of distribution following an IV 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.

Metabolism: The metabolism of triptorelin in humans is unknown, but is unlikely to involve hepatic microsomal enzymes (cytochrome P-450). However, the effect of triptorelin on the activity of other drug metabolizing enzymes is unknown. Thus far, no metabolites of trip-torelin 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 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. 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 non-renal clearance of triptorelin (patient anuric, Clcreat =0) was 76.2 mL/min, thus indicating that the nonrenal elimination of triptorelin is mainly dependent on the liver (see Special Populations).

Renal and Hepatic Impairment: After an IV injection of 0.5 mg trip-torelin peptide, the two distribution half-lives were unaffected by renal and hepatic impairment, but renal insufficiency led to a decrease in total triptorelin clearance proportional to the decrease in creatinine clearance as well as an increase in volume of distribution and consequently an increase in elimination half-life (Table 2). The decrease in triptorelin clearance was more pronounced in subjects with liver insufficiency, but the half-life was prolonged similarly in subjects with renal insufficiency, since the volume of distribution was only minimally increased.

Age and Race: The effects of age and race on triptorelin pharma-cokinetics have not been systematically studied. However, pharma-cokinetic data obtained in young healthy male volunteers aged 20 to 22 years with an elevated creatinine clearance (approximately 150 mL/min) indicates that triptorelin was eliminated twice as fast in this young population (see Special Populations, Renal and Hepatic Impairment) as compared to 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.

Pharmacokinetic Drug-Drug Interactions: No pharmacokinetic drug-drug interaction studies have been conducted with triptorelin (see PRECAUTIONS, Drug Interactions).

TRELSTAR^TM DEPOT 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 (71 mean). Patients received either TRELSTAR^TM DEPOT 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) were achieved in 91.2% of TRELSTAR^TM DEPOT patients at Day 29 and in 97.7% of patients at Day 57.

Maintenance of castration levels of serum testosterone from Day 57 through Day 253 was found in 96.4% of TRELSTAR^TM DEPOT patients.

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^TM DEPOT administration on Days 85 and 169. One hundred twenty-four of 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.