Quetiapine Fumarate (Page 10 of 14)
12.3 Pharmacokinetics
Adults
Quetiapine fumarate activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range, and quetiapine accumulation is predictable upon multiple dosing. Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine 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 to 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 is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with C and AUC values increased by 25% and 15%, respectively. max
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. , 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. In vitro
Metabolism and Elimination
Following a single oral dose of 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. 14
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. 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. In vitro
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 (2.3)]. Dosage and Administration
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 to 30 mL/min/1.73 m , n=8) had a 25% lower mean oral clearance than normal subjects (Clcr > 80 mL/min/1.73 m , 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 ]. 2 2 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 two 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 ]. and Dosage and Administration(2.4)Use in Specific Populations (8.7)
Drug-Drug Interaction Studies
assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 17 [ ]. The in vivo see and Dosage and Administration (2.5 and 2.6)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 |
enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on metabolism mediated by cytochromes CYP 1A2, 2C9, 2C19, 2D6 and 3A4. In vitro in vivo
Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam (Table 18) [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 | C and AUC of free valproic acid at steady-state was decreased by 10 to 12% max |
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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