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Therapeutic Classification: Antipsychotic.
Pharmacology: Pharmacodynamics: Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also reverses the action of dopamine agonists, measured either behaviorally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of dopamine D2 receptor blockade.
The results of animal studies predictive of EPS liability revealed that quetiapine causes only weak catalepsy at effective dopamine D2 receptor blocking doses, that quetiapine causes selective reduction in the firing of mesolimbic A10 dopaminergic neurones versus the A9 nigrostriatal neurones involved in motor function, and that quetiapine exhibits minimal dystonic liability in neuroleptic-sensitised monkeys.
Clinical efficacy: Clinical trials have demonstrated that quetiapine is effective when given twice a day. This is further supported by data from a positron emission tomography (PET) study which identified that 5HT2 and D2 receptor occupancy are maintained for up to 12 hours after dosing with quetiapine.
Schizophrenia: In clinical trials, quetiapine has been shown to be effective in the treatment of both positive and negative symptoms of schizophrenia. In one trial against chlorpromazine, and two against haloperidol, quetiapine showed similar short-term efficacy.
The results of three placebo-controlled clinical trials, including one that used a dose range of quetiapine of 75 to 750 mg/day, identified no difference between quetiapine and placebo in the incidence of EPS or use of concomitant anticholinergics.
Bipolar Mania: In clinical trials, quetiapine has been shown to be effective as monotherapy or as adjunct therapy in reducing manic symptoms in patients with bipolar mania. The mean last week median dose of quetiapine in responders, was approximately 600 mg and approximately 85% of the responders were in the dose range of 400 to 800 mg per day.
In four placebo-controlled trials, evaluating doses of quetiapine up to 800mg for the treatment of bipolar mania, two each in monotherapy and as adjunct therapy to lithium or valproate semisodium, there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics.
MECHANISM OF ACTION: Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interacts with a broad range of neurotransmitter receptors.
Quetiapine and norquetiapine exhibit affinity for serotonin (5HT2) and dopamine D1 and D2 receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to dopamine D2 receptors which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of quetiapine.
Additionally, norquetiapine has high affinity for the norepinenephrine transporter (NET).
Quetiapine and norquetiapine also have high affinity at histaminergic and adrenergic α1 receptors, with a lower affinity at adrenergic α2 and serotonin 5HT1A receptors. Quetiapine has no appreciable affinity at cholinergic muscarinic or benzodiazepine receptors.
Pharmacokinetics: Quetiapine is well absorbed and extensively metabolised following oral administration.
The bioavailability of quetiapine is not significantly affected by administration with food.
Quetiapine is approximately 83% bound to plasma proteins. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine. The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively.
The pharmacokinetics of quetiapine and norquetiapine are linear across the approved dosing range. The kinetics of quetiapine does not differ between men and women.
The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.
The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1.73m2) and in subjects with hepatic impairment (stable alcoholic cirrhosis), but the individual clearance values are within the range for normal subjects. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.
Quetiapine is extensively metabolised, with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled quetiapine. Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.
In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4.
Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50-fold higher than those observed at a dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug.
Toxicology: PRE-CLINICAL SAFETY DATA: Acute toxicity studies: Quetiapine has low acute toxicity. Findings in mice and rats after oral (500 mg/kg) or intraperitoneal (100 mg/kg) dosing were typical of an effective neuroleptic agent and included decreased motor activity, ptosis, loss of righting reflex, fluid around the mouth and convulsions.
Repeat-dose toxicity studies: In multiple-dose studies in rats, dogs and monkeys, anticipated central nervous system effects of an antipsychotic drug were observed with quetiapine (eg, sedation at lower doses and tremor, convulsions or prostration at higher exposures).
Hyperprolactinaemia, induced through the dopamine D2 receptor antagonist activity of quetiapine or its metabolites, varied between species but was most marked in the rat, and a range of effects consequent to this were seen in the 12-month study, including mammary hyperplasia, increased pituitary weight, decreased uterine weight and enhanced growth of females.
Reversible morphological and functional effects on the liver, consistent with hepatic enzyme induction, were seen in mouse, rat and monkey.
Thyroid follicular cell hypertrophy and concomitant changes in plasma thyroid hormone levels occurred in rat and monkey.
Pigmentation of a number of tissues, particularly the thyroid, was not associated with any morphological or functional effects.
Transient increases in heart rate, unaccompanied by an effect on blood pressure, occurred in dogs.
Posterior triangular cataracts seen after 6 months in dogs at 100 mg/kg/day were consistent with inhibition of cholesterol biosynthesis in the lens. No cataracts were observed in Cynomolgus monkeys dosed up to 225 mg/kg/day, nor in rodents.
Monitoring in clinical studies did not reveal drug-related corneal opacities in man.
No evidence of neutrophil reduction or agranulocytosis was seen in any of the toxicity studies.
Carcinogenicity studies: In the rat study (doses 0, 20, 75 and 250 mg/kg/day) the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinaemia.
In male rat (250 mg/kg/day) and mouse (250 and 750 mg/kg/day), there was an increased incidence of thyroid follicular cell benign adenomas, consistent with known rodent-specific mechanisms resulting from enhanced hepatic thyroxine clearance.
Reproduction studies: Effects related to elevated prolactin levels (marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate) were seen in rats, although these are not directly relevant to humans because of species differences in hormonal control of reproduction.
Quetiapine had no teratogenic effects.
Mutagenicity studies: Genetic toxicity studies with quetiapine show that it is not a mutagen or clastogen.
