Quinagolide (Norprolac(R)) is a novel, long-acting dopaminergic drug designed for use in hyperprolactinemia. The molecule is a octahydrobenzo[g]quinoline, which has neither an ergot nor an ergoline structure, and thus represents a third-generation prolactin inhibitor.
Unique among pituitary hormones, normal levels of prolactin are maintained through negative feedback action by the hypothalamic prolactin inhibiting factor which is the neurotransmitter dopamine. Among the dopamine receptor subtypes, the dopamine D-2 receptor on the pituitary lactotrope is specific to prolactin regulation. Hence, the use of dopaminergic drugs as prolactin inhibitors, and the rationale for the design of a D-2 receptor-specific drug.
Prolactin oversecretion can be caused by multiple factors that lead to dysfunction of the hypothalamic-pituitary regulatory system and result in uncontrolled activity of the lactotropes, with or without adenomatous tumor growth.
Clinical manifestations of hyperprolactinemia appear as disturbances of reproductive function, specifically menstrual cycle dysfunction, decreased libido in women and in men, impotence and sometimes galactorrhea. Large tumors may expand beyond the pituitary fossa, causing neurological as well as endocrinological symptoms.
The goals of treatment with a dopaminergic drug are to relieve symptoms, restore gonadal function and, when a large prolactinoma is present, to shrink the tumor.
Preclinical studies with quinagolide show it to be a potent and selective dopaminergic drug. The specificity of quinagolide for the D-2 receptor was demonstrated by receptor binding studies and by the use of selective and nonselective antagonists to reverse the quinagolide-induced prolactin inhibition by pituitary cells in vitro. Quinagolide shows no action on adrenergic or serotonin receptors, and its oral and parenteral activity in prolactin inhibition tests is 35-200 times greater than that of bromocriptine.
Early-phase studies in healthy volunteers show that quinagolide possesses 24-hour prolactin suppressant action, and that the drug's activity is specific to the pituitary lactotropic cells. In short- and long-term dose-ranging trials in patients with idiopathic or microadenoma-induced hyperprolactinemia quinagolide produced strong and sustained prolactin suppression in up to 93% of patients, with associated relief of galactorrhea and return of ovulatory menses in up to 97%. These studies showed that quinagolide is effective in lowering prolactin levels over a broad dose range, and that treatment should begin with a 1-week titration scheme followed by a basic maintenance dose of 0.075 mg once daily. At this dose, 70% of patients normalize, 75% of them within the first month. Titration to individual need can be done at approximately monthly intervals without affecting tolerability or safety.
The clinical efficacy and tolerability of quinagolide in hyperprolactinemic women with or without microadenoma was compared with the action of bromocriptine in a multicenter study with a double-blind phase of 6 months. After 6 months, all patients continued open-label treatment with quinagolide up to 24 months. The results of the double-blind period show that quinagolide is at least as effective as bromocriptine in suppressing prolactin and alleviating the symptoms of prolactin oversecretion. With quinagolide treatment alone, prolactin normalization occurred in 88% of patients patients by month 24, while regular menses were established and galactorrhea relieved in up to 95%, at doses similar to those of the earlier studies. Quinagolide was judged by patients and physicians to be better tolerated than bromocriptine, and there were statistically significantly fewer discontinuations (p <0.03) in the quinagolide group.
In 72% of patients with macroadenomas (>10 mm in diameter), prolactin was normalized at quinagolide doses less than 0.3 mg daily in the majority of patients. Clinical complaints disappeared as normoprolactinemia was attained Tumor shrinkage of more than 50% was registered in about 70% of the tumors, no direct correlation being observed between baseline tumor size or prolactin level, or length of quinagolide treatment.
The prolactin normalization rate inpatients who do not tolerate other dopaminergic drugs is 93%, and 57% in patients who are resistant to other drugs, predominantly bromocriptine.
In studies using radiolabeled drug quinagolide was shown to be rapidly and well absorbed after oral administration. The compound is extensively metabolized during its first pass, and more than 95% is excreted via urine and feces.
With therapeutic doses, a clinically significant prolactin-lowering effect occurs within 2 hours after ingestion, reaches a maximum within 4-6 hours, and is maintained for 24 hours. The effective bioavailability is almost 100%. No drug accumulation occurs during long-term treatment, and no loss of therapeutic effect is seen when patients are switched without treatment interruption from bromocriptine to quinagolide.
About 95% of patients are able to tolerate quinagolide. Adverse events are similar to those of other dopamine agonists, but are reported less often, are less severe, and tend to be self-limiting. Adverse events include nausea, headache and fatigue in more than 10% of patients, and abdominal discomfort, constipation and nasal stuffiness in fewer than 10%. Orthostatic hypotension has been rarely documented. No evidence of drug toxicity to any organ system has been recorded, The only clinically notable long-term effect has been a trend towards normalization in lipid metabolism when serum lipids were elevated at the beginning of quinagolide treatment.
The course and outcome of 169 pregnancies occurring during quinagolide development studies indicate that exposure to the drug during gestation does not increase the rates of spontaneous abortion, multiple pregnancy or fetal abnormalities.
In summary, quinagolide represents clear progress in dopamine agonist therapy because of its broad clinical efficacy and improved tolerability profile.