Mechanism of Action
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 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 LA to men with advanced prostate can-cer,
serum testosterone levels first increased, peaking on days 2-3, and declined
thereafter to low levels by weeks 3-4.
Pharmacokinetics
Results of pharmacokinetic investigations conducted in healthy men indicate
that after intravenous (IV) 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: Triptorelin pamoate is not active when given orally.
The pharmacokinetic parameters following a single IM injection of 11.25 mg of
TRELSTAR LA to 13 patients with prostate cancer are listed in Table 1.
Triptorelin did not accumulate over 9 months of treatment.
TABLE 1. PHARMACOKINETIC PARAMETERS (MEAN ± SD) FOLLOWING
INTRAMUSCULAR ADMINISTRATION OF TRELSTAR LA TO PATIENTS WITH PROSTATE CANCER
Dose
(No. of subjects) |
C max (0-85d)
(ng/mL) |
T max (1-85d)
(h) |
AUC(1-85d)
(h·ng/mL) |
| 11.25 mg (n=13) |
38.5 ± 10.5 |
2.9 ± 1.3 |
2268.0 ± 444.6 |
Distribution: The volume of distribution following a single 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 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 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 nonrenal 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).
Special Populations
Renal and Hepatic Impairment: After an IV bolus injection of
0.5 mg triptorelin 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. Patients with renal or hepatic impairment
had 2- to 4-fold higher exposure (AUC values) than young healthy males.
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) 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
N o pharmacokinetic drug-drug interaction studies have been conducted with
triptorelin (see PRECAUTIONS: DRUG INTERACTIONS).
Clinical Trials
TRELSTAR LA was studied in a randomized, active control trial of 346
men with advanced prostate cancer in South Africa. The clinical trial population
consisted of 48% Caucasian, 38% Black, and 15% Other. Men were between 45 and
96 years of age (71 mean). Patients received either TRELSTAR LA (n =
174) every 84 days for a total of up to 3 doses (maximum treatment period of
252 days) or Trelstar Depot (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.
TABLE 2. PHARMACOKINETIC PARAMETERS (MEAN ±SD) IN
HEALTHY VOLUNTEERS AND SPECIAL POPULATIONS
| Group |
Cmax (ng/mL) |
AUCinf
(h·g/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 |
Castration levels of serum testosterone ( ≤ 1.735 nmol/L) were achieved at
Day 29 in 167 of 171 (97.7%) of patients treated with TRELSTAR LA.
Maintenance of castration levels of serum testosterone from Day 57 through
Day 253 was found in 94.4% of patients treated with TRELSTAR LA.
Last updated on RxList: 5/6/2009