CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of quetiapine, as with other drugs having efficacy in the treatment of schizophrenia, is unknown. However, it is believed that this drug’s efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism, by quetiapine and its active metabolite N-desalkyl quetiapine.
Antagonism at receptors other than dopamine D2 and serotonin 5HT2 with similar or greater affinities may explain some of the other effects of quetiapine and N-desalkyl quetiapine; antagonism at histamine H1 receptors may explain the somnolence and antagonism at adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.
Pharmacodynamics
Quetiapine is an antagonist at multiple neurotransmitter receptors in the brain: serotonin 5HT1A and 5HT2 (IC50s=717 & 148nM respectively), dopamine D1 and D2 (IC50s=1268 & 329nM respectively), histamine H1 (IC50=30nM), and adrenergic α1 and α2 receptors (IC50s=94 & 271nM, respectively). Quetiapine has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC50s>5000 nM).
Pharmacokinetics
Following multiple dosing of quetiapine up to a total daily dose of 800 mg, administered in divided doses, the plasma concentration of quetiapine and N-desalkyl quetiapine, the major active metabolite of quetiapine, were proportional to the total daily dose. Accumulation is predictable upon multiple dosing. Steady-state mean Cmax and AUC of N-desalkyl quetiapine are about 21-27% and 46-56%, respectively of that observed for quetiapine. Elimination of quetiapine is mainly via hepatic metabolism. The mean-terminal half-life is approximately 7 hours for quetiapine and 9 to 12 hours for N-desalkyl quetiapine within the clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. SEROQUEL XR is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.
Absorption
Quetiapine fumarate reaches peak plasma concentrations approximately 6 hours following administration. SEROQUEL XR dosed once daily at steady-state has comparable bioavailability to an equivalent total daily dose of SEROQUEL administered in divided doses, twice daily. A high-fat meal was found to produce statistically significant increases in the SEROQUEL XR Cmax and AUC of 44% to 52% and 20% to 22%, respectively, for the 50-mg and 300-mg tablets. In comparison, a light meal had no significant effect on the Cmax or AUC of quetiapine. It is recommended that SEROQUEL XR be taken without food or with a light meal [ see Dosage and Administration (2)].
Distribution
Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 L/kg. Quetiapine is 83% bound to plasma proteins at therapeutic concentrations. In vitro, quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine.
Metabolism and Elimination
Following a single oral dose of 14C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively. The average dose fraction of free quetiapine and its major active metabolite is <5% excreted in the urine.
Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite and in the metabolism of its active metabolite N-desalkyl quetiapine.
Gender
There is no gender effect on the pharmacokinetics of quetiapine.
Race
There is no race effect on the pharmacokinetics of quetiapine.
Smoking
Smoking has no effect on the oral clearance of quetiapine.
Renal Insufficiency
Patients with severe renal impairment (CLcr=10-30 mL/min/1.73m2, n=8) had a 25% lower mean oral clearance than normal subjects (CLcr>80 mL/min/1.73m2, n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients.
Hepatic Insufficiency
Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In 2 of the 8 hepatically impaired patients, AUC and Cmax were 3 times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed [See Dosage And Administration (2)].
Drug-Drug Interactions
In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes P450 1A2, 2C9, 2C19, 2D6 and 3A4.
Quetiapine oral clearance is increased by the prototype cytochrome P450 3A4 inducer, phenytoin, and decreased by the prototype cytochrome P450 3A4 inhibitor, ketoconazole. Dose adjustment of quetiapine will be necessary if it is coadministered with phenytoin or ketoconazole [See Drug Interactions (7.1) and Dosage And Administration (2)].
Quetiapine oral clearance is not inhibited by the non-specific enzyme inhibitor, cimetidine.
Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam [See Drug Interactions ].
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in C57BL mice and Wistar rats. Quetiapine was administered in the diet to mice at doses of 20, 75, 250, and 750 mg/kg and to rats by gavage at doses of 25, 75, and 250 mg/kg for two years. These doses are equivalent to 0.1, 0.5, 1.5, and 4.5 times the maximum human dose (800 mg/day) on a mg/m2 basis (mice) or 0.3, 0.9, and 3.0 times the maximum human dose on a mg/m2 basis (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses of 250 and 750 mg/kg or 1.5 and 4.5 times the maximum human dose on a mg/m2 basis and in male rats at a dose of 250 mg/kg or 3.0 times the maximum human dose on a mg/m2 basis. Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (25, 75, and 250 mg/kg or 0.3, 0.9, and 3.0 times the maximum recommended human dose on a mg/m2 basis).
Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine, and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however, the results of these studies were not definitive. The relevance of the increases in thyroid follicular cell adenomas to human risk, through whatever mechanism, is unknown.
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum measurements in a 1-yr toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32- and 13-fold in male and female rats, respectively. Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown [see Warning and Precautions ].
Mutagenesis
The mutagenic potential of quetiapine was tested in six in vitro bacterial gene mutation assays and in an in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. However, sufficiently high concentrations of quetiapine may not have been used for all tester strains. Quetiapine did produce a reproducible increase in mutations in one Salmonella typhimurium tester strain in the presence of metabolic activation. No evidence of clastogenic potential was obtained in an in vitro chromosomal aberration assay in cultured human lymphocytes or in the in vivo micronucleus assay in rats.
Impairment of Fertility
Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or 0.6 and 1.8 times the maximum human dose on a mg/m2 basis. Drug related effects included increases in interval to mate and in the number of matings required for successful impregnation. These effects continued to be observed at 150 mg/kg even after a two-week period without treatment. The no-effect dose for impaired mating and fertility in male rats was 25 mg/kg, or 0.3 times the maximum human dose on a mg/m2 basis. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose of 50 mg/kg, or 0.6 times the maximum human dose on a mg/m2 basis. Drug-related effects included decreases in matings and in matings resulting in pregnancy, and an increase in the interval to mate. An increase in irregular estrus cycles was observed at doses of 10 and 50 mg/kg, or 0.1 and 0.6 times the maximum human dose on a mg/m2 basis. The no effect dose in female rats was 1 mg/kg, or 0.01 times the maximum human dose on a mg/m2 basis.
Animal Toxicology and/or Pharmacology
Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2 year carcinogenicity study. Doses were 10-250 mg/kg in rats, 75-750 mg/kg in mice; these doses are 0.1-3.0, and 0.1-4.5 times the maximum recommended human dose (on a mg/m2 basis), respectively. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown.
In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the maximum recommended human dose on a mg/m2 basis. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta 8 cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the maximum recommended human dose on a mg/m2 basis.
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