Quetiapine Fumarate Extended Release (Page 9 of 12)

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 C max 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. Quetiapine fumarate extended-release tablets 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 C max of the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and C max 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. Quetiapine fumarate extended-release tablets dosed once daily at steady state has comparable bioavailability to an equivalent total daily dose of quetiapine fumarate administered in divided doses, twice daily. A high-fat meal (approximately 800 to 1000 calories) was found to produce statistically significant increases in the quetiapine fumarate extended-release tablets C max 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 C max or AUC of quetiapine. It is recommended that quetiapine fumarate extended-release tablets 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 (CL cr =10-30 mL/min/1.73m 2 , n=8) had a 25% lower mean oral clearance than normal subjects (CL cr >80 mL/min/1.73m 2 , 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 C max 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, 2.6) and Drug Interactions (7.1)].

Table 25: The Effect of Other Drugs on the Pharmacokinetics of Quetiapine

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)].

Table 26: The Effect of Quetiapine on the Pharmacokinetics of Other Drugs

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

C max 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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