Clinical Pharmacokinetics of Quetiapine
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Quetiapine is a dibenzothiazepine derivative that has been evaluated for management of patients with the manifestations of psychotic disorders. In pharmacokinetic studies in humans, quetiapine was rapidly absorbed after oral administration, with median time to reach maximum observed plasma concentration ranging from 1 to 2 hours. The absolute bioavailability is unknown, but the relative bioavailability from orally administered tablets compared with a solution was nearly complete.
Food has minimal effects on quetiapine absorption. The drug is approximately 83% bound to serum proteins. Single and multiple dose studies have demonstrated linear pharmacokinetics in the clinical dose range (up to 375mg twice daily). The drug is eliminated with a mean terminal half-life of approximately 7 hours.
The primary route of elimination is through hepatic metabolism. In vitro studies show that quetiapine is predominantly metabolised by cytochrome P450 (CYP) 3A4. After administration of [14C]quetiapine, approximately 73% of the radioactivity was excreted in the urine and 21% in faeces. Quetiapine accounted for less than 1% of the excreted radioactivity. 11 metabolites formed through hepatic oxidation have been identified. Two were found to be pharmacologically active, but they circulate in plasma at 2 to 12% of the concentration of quetiapine and are unlikely to contribute substantially to the pharmacological effects of the drug.
The pharmacokinetics of quetiapine do not appear to be altered by cigarette smoking. Oral clearance declines with age, and was reduced in 2 of 8 patients with hepatic dysfunction but not in patients with renal impairment.
Quetiapine has no effect on the in vitro activity of CYP1A2, 2C9, 2C19, 2D6 and 3A4 at clinically relevant concentrations. The lack of effect of quetiapine on hepatic oxidation was confirmed in vivo by the lack of effect of quetiapine on antipyrine disposition. Quetiapine had no effect on serum lithium concentration. Phenytoin and thioridazine increase the clearance of quetiapine, and ketoconazole decreases clearance. No clinically significant effects of cimetidine, haloperidol, risperidone or imipramine on the pharmacokinetics of quetiapine were noted. Quetiapine dosage adjustment, therefore, may be necessary when coadministered with phenytoin, thioridazine or other potent CYP3A4 inducers or inhibitors.
The relationship between the therapeutic effects and the plasma concentrations of quetiapine has been investigated in a multicentre clinical trial. There was no statistically significant association between trough plasma quetiapine concentration and clinical response as measured by traditional assessments of psychotic symptom severity. Subsequent clinical studies of the plasma concentration versus effect relationships for quetiapine may help to further define guidelines for dosage regimen design.
- Goldstein J, Arvanitis L. ICI 204,636 (Seroquel): a dibenzothiazepine atypical antipsychotic. Review of preclinical pharmacology and highlights of Phase II clinical trials. CNS Drug Rev 1995; 1: 50–73 CrossRef
- Small JG, Hirsch SR, Arvanitis LA, et al. Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group. Arch Gen Psychiatry 1997; 54: 549–57 CrossRef
- Arvanitis LA, Miller BG. Multiple fixed doses of ’seroquel’ (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 1997; 42: 233–46 CrossRef
- Peuskens J, Link CG. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997; 96: 265–73 CrossRef
- Pullen RH, Palermo KM, Curtis MA. Determination of an antipsychotic agent (ICI 204,636) and its 7-hydroxy metabolite in human plasma by high-performance liquid chromatography and gas chromatography-mass spectrometry. J Chromatogr 1992; 573: 49–57 CrossRef
- Item 2F: Human pharmacokinetics and bioavailability. New drug application — Seroquel. Zeneca Ltd, 1996 May 21. Available from: URL: http://www.fda.gov/cder/regulatory/applications/nda.htm [Accessed 2001 Jul 2]
- Thyrum PT, Wong YWJ, Yeh C. Single-dose pharmacokinetics of quetiapine in subjects with renal or hepatic impairment. Prog Neuropsychopharmacol Biol Psychiatry 2000; 24: 521–33 CrossRef
- Seroquel™ (quetiapine fumarate) product package insert. Wilmington (DE): AstraZeneca Pharmaceuticals, 2001
- DeVane CL, Markowitz JS. Drugs as substances of metabolic enzymes: antipsychotics. In: Levy RH, Thummel KE, trager WF, et al., editors. Metabolic drug interactions. Baltimore (MD): Lippincott-Raven Press, 2000: 245–58
- Gefvert O, Bergstrom M, Langstrom B, et al. Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel) in patients with schizophrenia. Psychopharmacology (Berl) 1998; 135: 119–26 CrossRef
- Schmider J, Greenblatt DJ, von Moltke LL, et al. N-demethylation of amitriptyline in vitro: role of cytochrome P-450 3A (CYP3A) isoforms and effect of metabolic inhibitors. J Pharmacol Exp Ther 1995; 275: 592–7
- Strakowski SM, Keck Jr PE, Wong YWJ, et al. The effect of multiple doses of cimetidine on the steady-state pharmacokinetics of quetiapine in men with selected psychotic disorders. Psychopharmacology. In press
- Grimm SW, Stams KR, Bui K. In vitro prediction of potential metabolic drug interactions for Seroquel (quetiapine). American Psychiatric Association Annual Meeting; 1997 May 17–22; San Diego
- McConville BJ, Arvanitis LA, Thyrum PT, et al. Pharmacokinetics, tolerability, and clinical effectiveness of quetiapine fumarate: an open-label trial in adolescents with psychotic disorders. J Clin Psychiatry 2000; 61: 252–60 CrossRef
- Sotaniemi EA, Arranto AJ, Pelkonen O, et al. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther 1997; 61: 331–9 CrossRef
- Rowland M, Tozer TN. Intergratiom with kinetics. In: Rowland M, Tozer TN, editors. Clinical pharmacokinetics: concepts and applications. Malvern (PA): Lee and Febiger, 1991: 183
- Morse JL, Ewing BJ, Zuleski FR, et al. The disposition and metabolism of Seroquel (ICI 204, 636) in rat, dog, monkey, and man [abstract]. ISSX International Meeting; 1995 Aug 27–31; Seattle
- Potkin SG, Thyrum PT, Bera R, et al. Pharmacokinetics and safety of lithium co-administration with quetiapine [abstract]. Schizophr Res 1997; 24 (1/2): 199 CrossRef
- St Peter JV, Braeckman RA, Granneman GR, et al. The effect of zileuton on antipyrine and indocyanine green disposition. Clin Pharmacol Ther 1995; 57: 299–308 CrossRef
- Fabre LF, Wong YWJ, Yeh C, et al. The effect of multiple dosing of quetiapine on antipyrine metabolism in patients with schizophrenia. Wilmington (DE): Astrazeneca, 1996 (Data on file)
- Evaluation and Research Psychopharmacologic Drugs Advisory Committee. Food and Drug Administration, 1999. Available from: URL: http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3619t1.rtf [Accessed 2001 Jun 21]
- Wong YWJ, Ewing BJ, Thyrum PT, et al. The effect of phenytoin and cimetidine on the pharmacokinetics of Seroquel (quetiapine) [abstract]. American Psychiatric Association Annual Meeting; 1997 May 17–22; San Diego
- Wong YW, Yeh C, Thyrum PT. The effects of concomitant phenytoin administration on the steady-state pharmacokinetics of quetiapine. J Clin Psychopharmacol 2001; 21: 89–93 CrossRef
- Pichard L, Fabre I, Fabre G, et al. Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab Dispos 1990; 18: 595–606
- Somogyi A, Muirhead M. Pharmacokinetic interactions of cimetidine. Clin Pharmacokinet 1987; 12: 321–66 CrossRef
- Potkin SG, Thyrum PT, Yeh C, et al. Effect of fluoxetine and imipramine on the pharmacokinetics and tolerability of the antipsychotic quetiapine. J Clin Psychopharmacol. In press
- Potkin SG, Thyrum PT, Yeh C, et al. The safety and pharmacokinetics of quetiapine when co-administered with haloperidol, risperidone, or thioridazine. J Clin Psychopharmacol. In press
- Stoudemire A. New antidepressant drugs and the treatment of depression in the medically ill patient. Psychiatr Clin North Am 1996; 19: 495–514 CrossRef
- Fabre Jr LF, Arvanitis L, Pultz J, et al. ICI 204,636, a novel, atypical antipsychotic: early indication of safety and efficacy in patients with chronic and subchronic schizophrenia. Clin Ther 1995; 17: 366–78 CrossRef
- Kimko HC, Reele SSB, Holford NHG, et al. Prediction of the outcome of a Phase 3 clinical trial of an antischizophrenic agent (quetiapine fumarate) by simulation with a population pharmacokinetic and pharmacodynamic model. Clin Pharmacol Ther 2000; 68: 568–77 CrossRef
- Kapur S, Zipursky R, Jones C, et al. Apositron emission tomography study of quetiapine in schizophrenia. Arch Gen Psychiatry 2000; 57: 553–9 CrossRef
- King DJ, Link CG, Kowalcyk B. A comparison of bd and tid dose regimens of quetiapine (Seroquel) in the treatment of schizophrenia. Psychopharmacology (Berl) 1998; 137: 139–46 CrossRef
- Clinical Pharmacokinetics of Quetiapine
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