Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ
Pharmacotherapeutic group: Dopamine agonists
ATC code: N04BC06
Cabergoline is a dopaminergic ergoline derivative endowed with potent and long-lasting dopamine D2 receptor agonist properties. In rats the compound, acting at D2 dopamine receptors on pituitary lactotrophic cells, decreases PRL secretion at oral doses of 3-25 mcg/kg, and in vitro at a concentration of 45 pg/ml. In addition, cabergoline exerts a central dopaminergic effect via D2 receptor stimulation at doses higher than those effective in lowering serum PRL levels. Improvement of motor deficit in animal models of Parkinson’s disease was present at oral daily doses of 1-2.5 mg/kg in rats and at s.c. doses of 0.5-1 mg/kg in monkeys.
In healthy volunteers the administration of cabergoline at single oral doses of 0.3-2.5 mg was associated with a significant decrease in serum PRL levels. The effect is prompt (within 3 hours of administration) and persistent (up to 7-28 days). The PRL-lowering effect is dose-related both in terms of degree of effect and duration of action.
The pharmacodynamic actions of cabergoline not linked to the therapeutic effect relate only to blood pressure decrease. The maximal hypotensive effect of cabergoline as a single dose usually occurs during the first 6 hours after drug intake and is dose-dependent both in terms of maximal decrease and frequency.
The pharmacokinetic and metabolic profiles of cabergoline have been studied in healthy volunteers of both sexes, in female hyperprolactinemic patients and in parkinsonian patients. After oral administration of the labelled compound, radioactivity was rapidly absorbed from the gastrointestinal tract as the peak of radioactivity in plasma was between 0.5 and 4 hours. Ten days after administration about 18/20% and 55/72% of the radioactive dose (3H-cabergoline/14C-cabergoline) was recovered in urine and faeces, respectively. Unchanged drug in urine accounted for 2-3% of the dose.
In urine, the main metabolite identified was 6-allyl-8b-carboxy-ergoline, which accounted for 4-6% of the dose. Three additional metabolites were identified in urine, which accounted overall for less than 3% of the dose. The metabolites have been found to be much less potent than cabergoline as D2 dopamine receptor agonists in vitro.
The low urinary excretion of unchanged cabergoline has been confirmed also in studies with non-radioactive product. The elimination half-life of cabergoline, estimated from urinary excretion rates, is long (63-68 hours in healthy volunteers, 79-115 hours in hyperprolactinemic patients).
The pharmacokinetics of cabergoline seem to be dose-independent both in healthy volunteers (doses of 0.5-1.5 mg) and parkinsonian patients (steady state of daily doses up to 7 mg/day).
On the basis of the elimination half-life, steady state conditions should be achieved after 4 weeks, as confirmed by the mean peak plasma levels of cabergoline obtained after a single dose (37±8 pg/ml) and after a 4 week multiple-regimen (101±43 pg/ml). In vitro experiments showed that the drug at concentrations of 0.1-10 ng/ml is 41-42% bound to plasma proteins.
Food does not appear to affect absorption and disposition of cabergoline.
While renal insufficiency has been shown not to modify cabergoline kinetics, hepatic insufficiency of severe degree (>10 Child-Pugh score, maximum score 12) has been shown to be associated with an increase of AUC.
Almost all the findings noted throughout the series of preclinical safety studies are a consequence of the central dopaminergic effects or the long-lasting inhibition of PRL in rodents with a specific hormonal physiology different to man.
Preclinical safety studies of cabergoline indicate a consistent safety margin for this compound in rodents and in monkeys, as well as a lack of teratogenic, genotoxic or carcinogenic potential.
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