Skip to main content
SpringerLink
Log in

Pharmacokinetics and Tolerability of Extended-Release Quetiapine Fumarate in Han Chinese Patients with Schizophrenia

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

The extended-release formulation of quetiapine (quetiapine XR), which was developed to provide more convenient once-daily administration, has been widely studied to characterize its pharmacokinetics in Caucasian populations but has rarely been studied in an Asia population. This study was conducted to evaluate the pharmacokinetics and tolerability of quetiapine XR administered as a single dose (300 mg) and multiple doses (300, 600, and 800 mg) in Han Chinese patients with schizophrenia.

Methods

This was a single-center, open-label, single-dose and multiple-dose randomized study. Among the 55 randomized subjects, a total of 40 female or male patients in 300 mg (n = 13), 600 mg (n = 13), or 800 mg (n = 14) groups completed the study of quetiapine fumarate XR. The treatment phase consisted of 5 consecutive days and was preceded by a 1- to 2-day titration period for the 600 and 800 mg groups. Pharmacokinetic parameters for both quetiapine and N-desalkyl quetiapine (norquetiapine) were determined. The tolerability evaluation included adverse events (AEs) noted by monitoring, physical examinations, vital signs, and clinical laboratory tests.

Results

N-desalkyl quetiapine was formed from quetiapine with an approximate metabolite to parent ratio of 0.5 across the three dose groups. The geometric mean elimination half-life (t ½) of both quetiapine and N-desalkyl quetiapine was consistent for the three dosing groups (approximately 7 h for quetiapine and approximately 18 h for N-desalkyl quetiapine). The geometric mean maximum plasma concentrations (C max) at steady state (C max,ss) of quetiapine for the three groups were 467, 740, and 1,126 ng/mL, respectively, and for N-desalkyl quetiapine were 138, 262, and 426 ng/mL, respectively. The values for the geometric mean area under the plasma concentration–time curve over a dosing interval at the steady-state (AUCss) of quetiapine were 5,094, 7,685, and 13,237 ng·h/mL, respectively, and for N-desalkyl quetiapine were 2,284, 4,341, and 7,216 ng·h/mL, respectively. The apparent oral clearance (CL/F) of quetiapine at steady state appeared to be comparable across the three dose groups. The pharmacokinetics of quetiapine XR were dose-proportional across the dosage range employed. The most common AE was somnolence, but all of the reported AEs were mild. There were no serious AEs or other significant AEs.

Conclusion

Quetiapine fumarate XR has a dose-proportional pharmacokinetic profile at doses ranging from 300 to 800 mg once daily, and a slower time to reach C max and steady state after 3 days of sequential dosing. Therefore, it offers a simple and rapid dose-escalation option and more convenient once-daily administration. The three dosages of quetiapine fumarate XR were generally well-tolerated in this pharmacokinetic study of Han Chinese patients with schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig.2
Fig.3
Fig.4
Fig.5

Similar content being viewed by others

Reference

  1. Stroup TS, McEvoy JP, Swartz MS, et al. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull. 2003;29(1):15–31.

    Article  PubMed  Google Scholar 

  2. Fleischhacker WW, Keet IP, Kahn RS, et al. The European First Episode Schizophrenia Trial (EUFEST): rationale and design of the trial. Schizophr Res. 2005;78(2–3):147–56. doi:10.1016/j.schres.2005.06.004.

    Article  PubMed  Google Scholar 

  3. Perkins DO, Gu H, Weiden PJ, et al. Predictors of treatment discontinuation and medication nonadherence in patients recovering from a first episode of schizophrenia, schizophreniform disorder, or schizoaffective disorder: a randomized, double-blind, flexible-dose, multicenter study. J Clin Psychiatry. 2008;69(1):106–13.

    Article  CAS  PubMed  Google Scholar 

  4. Ascher-Svanum H, Faries DE, Zhu B, et al. Medication adherence and long-term functional outcomes in the treatment of schizophrenia in usual care. J Clin Psychiatry. 2006;67(3):453–60.

    Article  PubMed  Google Scholar 

  5. Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: our patients can do better. J Clin Psychiatry. 2003;64(11):1308–15.

    Article  PubMed  Google Scholar 

  6. Weiden PJ, Kozma C, Grogg A, et al. Partial compliance and risk of rehospitalization among California Medicaid patients with schizophrenia. Psychiatr Serv. 2004;55(8):886–91. doi:10.1176/appi.ps.55.8.886.

    Article  PubMed  Google Scholar 

  7. Borison RL, Arvanitis LA, Miller BG. ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. U.S. SEROQUEL Study Group. J Clin Psychopharmacol. 1996;16(2):158–69.

    Article  CAS  PubMed  Google Scholar 

  8. 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. Bio Psychiatry. 1997;42(4):233–46.

    Article  CAS  Google Scholar 

  9. 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(6):549–57.

    Article  CAS  PubMed  Google Scholar 

  10. Buckley PF. Efficacy of quetiapine for the treatment of schizophrenia: a combined analysis of three placebo-controlled trials. Curr Med Res Opin. 2004;20(9):1357–63. doi:10.1185/030079904125004510.

    Article  CAS  PubMed  Google Scholar 

  11. Robles O, Zabala A, Bombin I, et al. Cognitive efficacy of quetiapine and olanzapine in early-onset first-episode psychosis. Schizophr Bull. 2011;37(2):405–15. doi:10.1093/schbul/sbp062.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Riedel M, Spellmann I, Strassnig M, et al. Effects of risperidone and quetiapine on cognition in patients with schizophrenia and predominantly negative symptoms. Eur Arch Psychiatry Clin Neurosci. 2007;257(6):360–70. doi:10.1007/s00406-007-0739-x.

    Article  PubMed  Google Scholar 

  13. Urben S, Baumann P, Barcellona S, et al. Cognitive efficacy of quetiapine in early-onset first-episode psychosis: a 12-week open label trial. Psychiatr Q. 2012;83(3):311–24. doi:10.1007/s11126-011-9201-3.

    Article  PubMed  Google Scholar 

  14. Lee KU, Jeon YW, Lee HK, et al. Efficacy and safety of quetiapine for depressive symptoms in patients with schizophrenia. Hum Psychopharmacol. 2009;24(6):447–52. doi:10.1002/hup.1047.

    Article  CAS  PubMed  Google Scholar 

  15. Saller CF, Salama AI. Seroquel: biochemical profile of a potential atypical antipsychotic. Psychopharmacology (Berl). 1993;112(2–3):285–92.

    Article  CAS  PubMed  Google Scholar 

  16. Goldstein JM, Arvanitis LA. ICI 204,636 (Seroquel™): a dibenzothiazepine atypical antipsychotic. Review of preclinical pharmacology and highlights of phase II clinical trials. CNS Drug Rev. 1995;1(1):50–73.

    Article  CAS  Google Scholar 

  17. Jensen NH, Rodriguiz RM, Caron MG, et al. N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine’s antidepressant activity. Neuropsychopharmacology. 2008;33(10):2303–12. doi:10.1038/sj.npp.1301646.

    Article  CAS  PubMed  Google Scholar 

  18. Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry. 2005;66(1):111–21.

    Article  CAS  PubMed  Google Scholar 

  19. Altamura AC, Salvadori D, Madaro D, et al. Efficacy and tolerability of quetiapine in the treatment of bipolar disorder: preliminary evidence from a 12-month open-label study. J Affect Disord. 2003;76(1–3):267–71.

    Article  CAS  PubMed  Google Scholar 

  20. DeVane CL, Nemeroff CB. Clinical pharmacokinetics of quetiapine. Clin Pharmacokinet. 2001;40(7):509–22.

    Article  CAS  PubMed  Google Scholar 

  21. Nemeroff CB, Kinkead B, Goldstein J. Quetiapine: preclinical studies, pharmacokinetics, drug interactions, and dosing. J Clin Psychiatry. 2002;63(Suppl 13):5–11.

    CAS  PubMed  Google Scholar 

  22. Mauri MC, Volonteri LS, Fiorentini A, et al. Two weeks’ quetiapine treatment for schizophrenia, drug-induced psychosis and borderline personality disorder: a naturalistic study with drug plasma levels. Expert Opin Pharmacother. 2007;8(14):2207–13. doi:10.1517/14656566.8.14.2207.

    Article  CAS  PubMed  Google Scholar 

  23. AstraZeneca. Seroquel IR prescribing information. 2013. http://www1.astrazeneca-us.com/pi/seroquel.pdf. Accessed 26 Jul 2013.

  24. Diaz E, Neuse E, Sullivan MC, et al. Adherence to conventional and atypical antipsychotics after hospital discharge. J Clin Psychiatry. 2004;65(3):354–60.

    Article  PubMed  Google Scholar 

  25. Medic G, Higashi K, Littlewood KJ, et al. Dosing frequency and adherence in chronic psychiatric disease: systematic review and meta-analysis. Neuropsychiatr Dis Treat. 2013;9:119–31. doi:10.2147/NDT.S39303.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Figueroa C, Brecher M, Hamer-Maansson JE, et al. Pharmacokinetic profiles of extended release quetiapine fumarate compared with quetiapine immediate release. Prog Neuropsychopharmacol Bio Psych. 2009;33(2):199–204. doi:10.1016/j.pnpbp.2008.09.026.

    Article  CAS  Google Scholar 

  27. Meulien D, Huizar K, Brecher M. Safety and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: pooled data from randomised, double-blind, placebo-controlled studies. Hum Psychopharmacol. 2010;25(2):103–15. doi:10.1002/hup.1091.

    Article  CAS  PubMed  Google Scholar 

  28. Kahn RS, Schulz SC, Palazov VD, et al. Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68(6):832–42.

    Article  CAS  PubMed  Google Scholar 

  29. Möller HJ, Johnson S, Mateva T, et al. Evaluation of the feasibility of switching from immediate release quetiapine to extended release quetiapine fumarate in stable outpatients with schizophrenia. Int Clin Psychopharmacol. 2008;23(2):95–105. doi:10.1097/YIC.0b013e3282f2d42c.

    Article  PubMed  Google Scholar 

  30. Peuskens J, Trivedi J, Malyarov S, et al. Prevention of schizophrenia relapse with extended release quetiapine fumarate dosed once daily: a randomized, placebo-controlled trial in clinically stable patients. Psychiatry (Edgmont). 2007;4(11):34–50.

    PubMed Central  PubMed  Google Scholar 

  31. El-Khalili N. Update on extended release quetiapine fumarate in schizophrenia and bipolar disorders. Neuropsychiatric Dis Treat. 2012;8:523–36. doi:10.2147/NDT.S14369.

    Article  CAS  Google Scholar 

  32. Johnson JA. Influence of race or ethnicity on pharmacokinetics of drugs. J Pharm Sci. 1997;86(12):1328–33. doi:10.1021/js9702168.

    Article  CAS  PubMed  Google Scholar 

  33. Lin Y, Anderson GD, Kantor E, et al. Differences in the urinary excretion of 6-beta-hydroxycortisol/cortisol between Asian and Caucasian women. J Clin Pharmacol. 1999;39(6):578–82.

    Article  CAS  PubMed  Google Scholar 

  34. Yu KS, Cho JY, Shon JH, et al. Ethnic differences and relationships in the oral pharmacokinetics of nifedipine and erythromycin. Clin Pharmacol Ther. 2001;70(3):228–36. doi:10.1067/mcp.2001.117703.

    Article  CAS  PubMed  Google Scholar 

  35. Juckel G, Winter H, Ståhle L, et al. 317–The pharmacokinetics of extended release quetiapine fumarate are not affected by a light meal. Schizophr Res. 2008;98:163–4.

    Article  Google Scholar 

  36. Datto C, Berggren L, Patel JB, et al. Self-reported sedation profile of immediate-release quetiapine fumarate compared with extended-release quetiapine fumarate during dose initiation: a randomized, double-blind, crossover study in healthy adult subjects. Clin Ther. 2009;31(3):492–502. doi:10.1016/j.clinthera.2009.03.002.

    Article  CAS  PubMed  Google Scholar 

  37. Riesenberg RA, Baldytcheva I, Datto C. Self-reported sedation profile of quetiapine extended-release and quetiapine immediate-release during 6-day initial dose escalation in bipolar depression: a multicenter, randomized, double-blind, phase IV study. Clin Ther. 2012;34(11):2202–11. doi:10.1016/j.clinthera.2012.09.002.

    Article  CAS  PubMed  Google Scholar 

  38. Bui K, Earley W, Nyberg S. Pharmacokinetic profile of the extended-release formulation of quetiapine fumarate (quetiapine XR): clinical implications. Curr Med Res Opin. 2013;29(7):813–25. doi:10.1185/03007995.2013.794774.

    Article  CAS  PubMed  Google Scholar 

  39. Eriksson L, Hallerback T, Jorgensen L, et al. Use of quetiapine XR and quetiapine IR in clinical practice for hospitalized patients with schizophrenia: a retrospective study. Ther Adv Pychopharmacol. 2012;2(6):217–26. doi:10.1177/2045125312453935.

    Article  CAS  Google Scholar 

  40. Winter HR, Earley WR, Hamer-Maansson JE, et al. Steady-state pharmacokinetic, safety, and tolerability profiles of quetiapine, norquetiapine, and other quetiapine metabolites in pediatric and adult patients with psychotic disorders. J Child Adolesc Psychopharmacol. 2008;18(1):81–98. doi:10.1089/cap.2007.0084.

    Article  PubMed  Google Scholar 

  41. Aichhorn W, Marksteiner J, Walch T, et al. Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol. 2006;21(2):81–5.

    Article  PubMed  Google Scholar 

  42. AstraZeneca. Seroquel XR prescribing information. 2013. http://www1.astrazeneca-us.com/pi/seroquelxr.pdf. Accessed 26 Jul 2013.

  43. Fisher DS, Handley SA, Flanagan RJ, et al. Plasma concentrations of quetiapine, N-desalkylquetiapine, o-desalkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide in relation to quetiapine dose, formulation, and other factors. Ther Drug Monit. 2012;34(4):415–21. doi:10.1097/FTD.0b013e3182603f62.

    CAS  PubMed  Google Scholar 

  44. Gandhi M, Aweeka F, Greenblatt RM, et al. Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol. 2004;44:499–523. doi:10.1146/annurev.pharmtox.44.101802.121453.

    Article  CAS  PubMed  Google Scholar 

  45. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol. 1992;44(2):275–83.

    Article  CAS  PubMed  Google Scholar 

  46. Zhu B, Liu ZQ, Chen GL, et al. The distribution and gender difference of CYP3A activity in Chinese subjects. Br J Clin Pharmacol. 2003;55(3):264–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Parkinson A, Mudra DR, Johnson C, et al. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol. 2004;199(3):193–209. doi:10.1016/j.taap.2004.01.010.

    Article  CAS  PubMed  Google Scholar 

  48. Fletcher CV, Acosta EP, Strykowski JM. Gender differences in human pharmacokinetics and pharmacodynamics. J Adolesc Health. 1994;15(8):619–29.

    Article  CAS  PubMed  Google Scholar 

  49. Bigos KL, Pollock BG, Stankevich BA, et al. Sex differences in the pharmacokinetics and pharmacodynamics of antidepressants: an updated review. Gen Med. 2009;6(4):522–43. doi:10.1016/j.genm.2009.12.004.

    Article  Google Scholar 

  50. Wolbold R, Klein K, Burk O, et al. Sex is a major determinant of CYP3A4 expression in human liver. Hepatology. 2003;38(4):978–88. doi:10.1053/jhep.2003.50393.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank all of the subjects, investigators, and the medical, nursing and laboratory staff who participated in the study included in this paper.

Conflict of interest

This study was funded by AstraZeneca Pharmaceutical Research & Development. Dr. Tianmei Si was the principal investigator for this study, and has received research grants from Johnson & Johnson, AstraZeneca, and Pfizer. The other authors have no conflicts of interest to declare.

Role of funding source

AstraZeneca Pharmaceutical Research & Development funded this study and was responsible for the study design and data collection. The authors were responsible for the data analysis and its interpretation, and writing this manuscript. The sponsor was also responsible for deciding to publish the data before submission of the article.

Author information

Authors and Affiliations

  1. Department of Clinical Psychopharmacology, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health, Haidian District, Huayuanbeilu 51#, Beijing, 100191, People’s Republic of China

    Qian Li, Yun Ai Su, Yi Liu & Tian Mei Si

  2. Center for Psychiatric Research, Beijing Huilongguan Hospital, Beijing, China

    Jing Xu Chen, Yun Long Tan & Fu De Yang

Authors
  1. Qian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun Ai Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Xu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yun Long Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fu De Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tian Mei Si
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tian Mei Si.

Additional information

Q. Li and Y. A. Su contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Q., Su, Y.A., Liu, Y. et al. Pharmacokinetics and Tolerability of Extended-Release Quetiapine Fumarate in Han Chinese Patients with Schizophrenia. Clin Pharmacokinet 53, 455–465 (2014). https://doi.org/10.1007/s40262-013-0127-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-013-0127-9

Keywords

Search

Navigation