SEROQUEL XR (Page 9 of 14)
12.3 Pharmacokinetics
Adults
Following multiple dosing of quetiapine up to a total daily dose of 800 mg, administered in divided doses, the plasma concentration of quetiapine and norquetiapine, 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 norquetiapine 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 approximately 12 hours for norquetiapine 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.
Children and Adolescents
At steady state the pharmacokinetics of the parent compound, in children and adolescents (10-17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and Cmax of the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and Cmax were 45% and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children and adolescents and adults [see Use in Specific Populations (8.4)].
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 (approximately 800 to 1000 calories) 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 (approximately 300 calories) 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 (2.1)].
Distribution
Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 L/kg. It 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 14 C-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 norquetiapine.
Age
Oral clearance of quetiapine was reduced by 40% in elderly patients (≥ 65 years, n = 9) compared to young patients (n = 12), and dosing adjustment may be necessary [see Dosage and Administration (2.3)].
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 [see Use in Specific Populations (8.6)].
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 (2.4) and Use in Specific Populations (8.7)].
Drug-Drug Interaction Studies
The in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 25 [see Dosage and Administration (2.5 and 2.6) and Drug Interactions (7.1)].
Coadministered drug | Dose schedules | Effect on quetiapine pharmacokinetics | |
Coadministered drug | Quetiapine | ||
Phenytoin | 100 mg three times daily | 250 mg three times daily | 5 fold increase in oral clearance |
Divalproex | 500 mg twice daily | 150 mg twice daily | 17% increase mean max plasma concentration at steady state. No effect on absorption or mean oral clearance |
Thioridazine | 200 mg twice daily | 300 mg twice daily | 65% increase in oral clearance |
Cimetidine | 400 mg three times daily for 4 days | 150 mg three times daily | 20% decrease in mean oral clearance |
Ketoconazole (potent CYP 3A4 inhibitor) | 200 mg once daily for 4 days | 25 mg single dose | 84% decrease in oral clearance resulting in a 6.2 fold increase in AUC of quetiapine |
Fluoxetine | 60 mg once daily | 300 mg twice daily | No change in steady state PK |
Imipramine | 75 mg twice daily | 300 mg twice daily | No change in steady state PK |
Haloperidol | 7.5 mg twice daily | 300 mg twice daily | No change in steady state PK |
Risperidone | 3 mg twice daily | 300 mg twice daily | No change in steady state PK |
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 CYP 1A2, 2C9, 2C19, 2D6 and 3A4. Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam (Table 26) [see Drug Interactions (7.2)].
Coadministered drug | Dose schedules | Effect on other drugs pharmacokinetics | |
Coadministered drug | Quetiapine | ||
Lorazepam | 2 mg, single dose | 250 mg three times daily | Oral clearance of lorazepam reduced by 20% |
Divalproex | 500 mg twice daily | 150 mg twice daily | Cmax and AUC of free valproic acid at steady-state was decreased by 10-12% |
Lithium | Up to 2400 mg/day given in twice daily doses | 250 mg three times daily | No effect on steady-state pharmacokinetics of lithium |
Antipyrine | 1 g, single dose | 250 mg three times daily | No effect on clearance of antipyrine or urinary recovery of its metabolites |
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