Chemical formula: C₂₁H₂₅N₃O₂S Molecular mass: 383.507 g/mol PubChem compound: 5002
Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1- and D2-receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2-receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal undesirable effect (EPS) liability of quetiapine prolonged release tablets compared to typical antipsychotics.
Quetiapine and norquetiapine have no appreciable affinity at benzodiazepine receptors but high affinity at histaminergic and adrenergic alpha1 receptors moderate affinity at adrenergic alpha2 receptors. Quetiapine also has low or no affinity for muscarinic receptors, while norquetiapine has moderate to high affinity at several muscarinic receptors, which may explain anti-cholinergic (muscarinic effects). Inhibition of NET and partial agonist action at 5HT1A sites by norquetiapine may contribute to quetiapine prolonged release tablet therapeutic efficacy as an antidepressant.
Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2-receptor blockade.
In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2-receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2-receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol-sensitised or drug-naive Cebus monkeys after acute and chronic administration.
Quetiapine is well absorbed following oral administration. Quetiapine prolonged-release tablets achieves peak quetiapine and norquetiapine plasma concentrations at approximately 6 hours after administration (Tmax). Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.
The pharmacokinetics of quetiapine and norquetiapine are linear and dose-proportional for doses up to 800 mg administered once daily. When Quetiapine Prolonged-release Tablets administered once daily is compared to the same total daily dose of immediate-release quetiapine fumarate (Quetiapine immediate release tablet) administered twice daily, the area under the plasma concentration-time curve (AUC) is equivalent, but the maximum plasma concentration (Cmax) is 13% lower at steady state. When quetiapine prolonged-release tablets is compared to quetiapine immediate release, the norquetiapine metabolite AUC is 18% lower.
In a study examining the effects of food on the bioavailability of quetiapine, a high-fat meal was found to produce statistically significant increases in the Quetiapine Prolonged-release Tablets Cmax and AUC of approximately 50% and 20% respectively., It cannot be excluded that the effect of a high fat meal on the formulation may be larger. In comparison, a light meal had no significant effect on the Cmax or AUC of quetiapine. It is recommended that quetiapine is taken once daily without food.
Quetiapine is approximately 83% bound to plasma proteins.
Quetiapine is extensively metabolised by the liver, with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled quetiapine.
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. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.
The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively. Approximately 73% of a radiolabelled drug was excreted in the urine and 21% in the faeces with less than 5% of the total radioactivity representing unchanged drug-related material. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.
The pharmacokinetics 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/1.73 m²), but the individual clearance values are within the range for normal subjects.
The mean quetiapine plasma clearance decreases with approximately 25% in persons with known hepatic impairment (stable alcoholcirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients.
Pharmacokinetic data were sampled in 9 children aged 10-12 years old and 12 adolescents, who were on steady-state treatment with 400 mg quetiapine twice daily. At steady-state, the dose-normalised plasma levels of the parent compound, quetiapine, in children and adolescents (10-17 years of age) were in general similar to adults, though Cmax in children was at the higher end of the range observed in adults. The AUC and Cmax for the active metabolite, norquetiapine, were higher, approximately 62% and 49% in children (10-12 years), respectively and 28% and 14% in adolescents (13-17 years), respectively, compared to adults.
No information is available for quetipine prolonged-release tablets in children and adolescents.
There was no evidence of genotoxicity in a series of in vitro and in vivo genotoxicity studies. In laboratory animals at a clinically relevant exposure level the following deviations were seen, which as yet have not been confirmed in long-term clinical research:
In rats, pigment deposition in the thyroid gland has been observed; in cynomolgus monkeys thyroid follicular cell hypertrophy, a lowering in plasma T3 levels, decreased haemoglobin concentration and a decrease of red and white blood cell count have been observed; and in dogs lens opacity and cataracts.
In an embryofoetal toxicity study in rabbits the foetal incidence of carpal/tarsal flexure was increased. This effect occurred in the presence of overt maternal effects such as reduced body weight gain. These effects were apparent at maternal exposure levels similar or slightly above those in humans at the maximal therapeutic dose. The relevance of this finding for humans is unknown.
In a fertility study in rats, marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate were seen. These effects are related to elevated prolactin levels and not directly relevant to humans because of species differences in hormonal control of reproduction.
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