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.
Similar content being viewed by others
Reference
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.
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.
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.
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.
Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: our patients can do better. J Clin Psychiatry. 2003;64(11):1308–15.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Saller CF, Salama AI. Seroquel: biochemical profile of a potential atypical antipsychotic. Psychopharmacology (Berl). 1993;112(2–3):285–92.
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.
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.
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.
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.
DeVane CL, Nemeroff CB. Clinical pharmacokinetics of quetiapine. Clin Pharmacokinet. 2001;40(7):509–22.
Nemeroff CB, Kinkead B, Goldstein J. Quetiapine: preclinical studies, pharmacokinetics, drug interactions, and dosing. J Clin Psychiatry. 2002;63(Suppl 13):5–11.
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.
AstraZeneca. Seroquel IR prescribing information. 2013. http://www1.astrazeneca-us.com/pi/seroquel.pdf. Accessed 26 Jul 2013.
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.
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.
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.
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.
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.
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.
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.
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.
Johnson JA. Influence of race or ethnicity on pharmacokinetics of drugs. J Pharm Sci. 1997;86(12):1328–33. doi:10.1021/js9702168.
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.
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.
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.
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.
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.
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.
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.
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.
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.
AstraZeneca. Seroquel XR prescribing information. 2013. http://www1.astrazeneca-us.com/pi/seroquelxr.pdf. Accessed 26 Jul 2013.
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.
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.
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.
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.
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.
Fletcher CV, Acosta EP, Strykowski JM. Gender differences in human pharmacokinetics and pharmacodynamics. J Adolesc Health. 1994;15(8):619–29.
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.
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.
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
Corresponding author
Additional information
Q. Li and Y. A. Su contributed equally to this work.
Rights 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
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40262-013-0127-9