CLINICAL PHARMACOLOGY
Mechanism of Action
The secretion of prolactin by the anterior pituitary
is mainly under hypothalmic inhibitory control, likely
exerted through release of dopamine by tuberoinfundibular
neurons. Cabergoline is a long-acting dopamine receptor
agonist with a high affinity for D2 receptors. Results
of in vitro studies demonstrate that cabergoline exerts
a direct inhibitory effect on the secretion of prolactin
by rat pituitary lactotrophs. Cabergoline decreased serum
prolactin levels in reserpinized rats. Receptor-binding
studies indicate that cabergoline has low affinity for
dopamine D1,a1,- and a2-
adrenergic, and 5-HT1- and 5-HT2-serotonin receptors.
Clinical Studies
The prolactin-lowering efficacy of DOSTINEX was demonstrated
in hyperprolactinemic women in two randomized, double-blind,
comparative studies, one with placebo and the other with
bromocriptine. In the placebo-controlled study (placebo
n=20; cabergoline n=168), DOSTINEX produced a dose-related
decrease in serum prolactin levels with prolactin normalized
after 4 weeks of treatment in 29%, 76%, 74% and 95% of
the patients receiving 0.125, 0.5, 0.75, and 1.0 mg twice
weekly respectively.
In the 8-week, double-blind period of the comparative
trial with bromocriptine (cabergoline n=223; bromocriptine
n=236 in the intent-to-treat analysis), prolactin was
normalized in 77% of the patients treated with DOSTINEX
at 0.5 mg twice weekly compared with 59% of those treated
with bromocriptine at 2.5 mg twice daily. Restoration
of menses occurred in 77% of the women treated with DOSTINEX,
compared with 70% of those treated with bromocriptine.
Among patients with galactorrhea, this symptom disappeared
in 73% of those treated with DOSTINEX compared with 56%
of those treated with bromocriptine.
Pharmacokinetics
Absorption: Following single
oral doses of 0.5 mg to 1.5 mg given to 12 healthy adult
volunteers, mean peak plasma levels of 30 to 70 picograms
(pg)/mL of cabergoline were observed within 2 to 3 hours.
Over the 0.5- to- 7 mg dose range, cabergoline plasma
levels appeared to be dose-proportional in 12 healthy
adult volunteers and nine adult parkinsonian patients.
A repeatdose study in 12 healthy volunteers suggests that
steady-state levels following a once-weekly dosing schedule
are expected to be twofold to threefold higher than after
a single dose. The absolute bioavailability of cabergoline
is unknown. A significant fraction of the administered
dose undergoes a first-pass effect. The elimination half-life
of cabergoline estimated from urinary data of 12 healthy
subjects ranged between 63 to 69 hours. The prolonged
prolactin-lowering effect of cabergoline may be related
to its slow elimination and long half-life.
Distribution: In animals, based
on total radioactivity, cabergoline (and/or its metabolites)
has shown extensive tissue distribution. Radioactivity
in the pituitary exceeded that in plasma by >100-fold
and was eliminated with a half-life of approximately 60
hours. This finding is consistent with the long-lasting
prolactin-lowering effect of the drug. Whole body autoradiography
studies in pregnant rats showed no fetal uptake but high
levels in the uterine wall. Significant radioactivity
(parent plus metabolites) detected in the milk of lactating
rats suggests a potential for exposure to nursing infants.
The drug is extensively distributed throughout the body.
Cabergoline is moderately bound (40% to 42%) to human
plasma proteins in a concentration-independent manner.
Concomitant dosing of highly protein-bound drugs is unlikely
to affect its disposition.
Metabolism: In both animals
and humans, cabergoline is extensively metabolized, predominately
via hydrolysis of the acylurea bond or the urea moiety.
Cytochrome P-450 mediated metabolism appears to be minimal.
Cabergoline does not cause enzyme induction and/or inhibition
in the rat. Hydrolysis of the acylurea or urea moiety
abolishes the prolactin-lowering effect of cabergoline,
and major metabolites identified thus far do not contribute
to the therapeutic effect.
Excretion: After oral dosing
of radioactive cabergoline to five healthy volunteers,
approximately 22% and 60% of the dose was excreted within
20 days in the urine and feces, respectively. Less than
4% of the dose was excreted unchanged in the urine. Nonrenal
and renal clearances for cabergoline are about 3.2 L/min
and 0.08 L/min, respectively. Urinary excretion in hyperprolactinemic
patients was similar.
Special Populations
Renal Insufficiency: The pharmacokinetics
of cabergoline were not altered in 12 patients with moderate-to-severe
renal insufficiency as assessed by creatinine clearance.
Hepatic Insufficiency: In 12
patients with mild-to-moderate hepatic dysfunction (Child-Pugh
score £10), no effect on mean cabergoline Cmax or
area under the plasma concentration curve (AUC) was observed.
However, patients with severe insufficiency (Child-Pugh
score >10) show a substantial increase in the mean
cabergoline Cmax and AUC, and thus necessitate caution.
Elderly: Effect of age on the
pharmacokinetics of cabergoline has not been studied.
Food-Drug Interaction
In 12 healthy adult volunteers, food did not alter cabergoline
kinetics.
Pharmacodynamics
Dose response with inhibition of plasma prolactin, onset
of maximal effect, and duration of effect has been documented
following single cabergoline doses to healthy volunteers
(0.05 to 1.5 mg) and hyperprolactinemic patients (0.3
to 1 mg). In volunteers, prolactin inhibition was evident
at doses >0.2 mg, while doses ³0.5 mg caused maximal
suppression in most subjects. Higher doses produce prolactin
suppression in a greater proportion of subjects and with
an earlier onset and longer duration of action. In 12
healthy volunteers, 0.5, 1, and 1.5 mg doses resulted
in complete prolactin inhibition, with a maximum effect
within 3 hours in 92% to 100% of subjects after the 1
and 1.5 mg doses compared with 50% of subjects after the
0.5 mg dose.
In hyperprolactinemic patients (N=51), the maximal prolactin
decrease after a 0.6 mg single dose of cabergoline was
comparable to 2.5 mg bromocriptine; however, the duration
of effect was markedly longer (14 days vs 24 hours). The
time to maximal effect was shorter for bromocriptine than
cabergoline (6 hours vs 48 hours).
In 72 healthy volunteers, single or multiple doses (up
to 2 mg) of cabergoline resulted in selective inhibition
of prolactin with no apparent effect on other anterior
pituitary hormones (GH, FSH, LH, ACTH, and TSH) or cortisol.
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