Population Pharmacokinetics, Safety and Tolerability of Extended-Release Bupropion and Its Three Metabolites in Chinese Healthy Volunteers

  • Fan Zhang
  • Yan Li
  • Jingqiu Hu
  • Jinhua Zhong
  • Huafang LiEmail author
Original Research Article


Background and Objective

Bupropion is used for the treatment of major depressive disorder. We determined the pharmacokinetics, safety, and tolerability of extended-release bupropion XL in healthy Chinese volunteers.


This open-label, single-center pharmacokinetic study was conducted between May 2016 and June 2016. Eligible volunteers received bupropion XL 150 mg once daily for 5 days, then 300 mg once daily from days 6 to 14. Pharmacokinetic parameters were evaluated after first and repeated doses by non-compartmental and population pharmacokinetic analyses.


Fifteen out of 16 enrolled volunteers completed the study. The geometric mean of the bupropion area under the concentration–time curve from 0 to 24 h (AUC0–24) was 498.2 and 1,165.7 h·ng/mL on days 1 and 14, respectively; maximum plasma concentration (Cmax) was 49.9 ng/mL on day 1 and steady-state maximum observed plasma concentration (Css_max) was 111.9 ng/mL on day 14. Among the three metabolites, hydroxybupropion showed the highest AUC0–24 and Cmax. The population pharmacokinetic model findings indicated an apparent oral clearance of 221 L/h for bupropion in a typical healthy 60.9-kg Chinese volunteer.


This was the first pharmacokinetic study for bupropion XL and its active metabolites in the Chinese population. The AUC and Cmax of bupropion XL and its three metabolites increased approximately in a dose-proportional manner with an increase from 150 mg to 300 mg. Adverse events were similar to those reported in studies outside China. A population pharmacokinetic model was developed for bupropion XL, with pharmacokinetics of bupropion adequately described by a two-compartment model with first-order absorption and linear elimination plus lag time.

Trial Registration Number




The authors thank all the study participants and trial site staff who were involved in the conduct of this trial. The authors also thank Yucheng Sheng (GSK), for calculating AUC0-∞ for bupropion after single-dose administration of 150 mg and 300 mg through simulation, and Pravin Bolshete (TATA Consultancy Services, India), for providing medical writing assistance.

Compliance with ethical standards

Conflicts of interest

Fan Zhang, Jingqiu Hu, and Jinhua Zhong were employees of GSK while conducting the study and during manuscript development. The remaining authors have no conflict of interest to declare.


This study and medical writing assistance was funded by GlaxoSmithKline (China) R&D Company Limited.

Informed consent

Each study volunteer provided written informed consent before any study-specific procedure was performed.

Author Contributions

All authors participated in the conception or study design and data interpretation. YL and HL also helped in acquisition of data. All the authors participated in drafting the manuscript, and read, revised and approved the final manuscript for submission.

Data sharing

Anonymized individual participant data and study documents can be requested for further research from

Supplementary material

13318_2018_537_MOESM1_ESM.pdf (191 kb)
Supplementary material 1 (PDF 191 kb)


  1. 1.
    Nglazi MD, Joubert JD, Stein DJ, et al. Epidemiology of major depressive disorder in South Africa (1997-2015): a systematic review protocol. BMJ Open. 2016;6:es011749.CrossRefGoogle Scholar
  2. 2.
    Low W, Azmi S, Li Y, et al. Prevalence of major depressive disorder in China. Value Health. 2014;[Abstract:PMH9].Google Scholar
  3. 3.
    World Population Prospects: The 2017 Revision. Available from Accessed 02 May 2018.
  4. 4.
    Lepine BA, Moreno RA, Campos RN, et al. Treatment-resistant depression increases health costs and resource utilization. Rev Bras Psiquiatr. 2012;34:379–88.CrossRefPubMedGoogle Scholar
  5. 5.
    Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.CrossRefGoogle Scholar
  6. 6.
    Hou Z, Jiang W, Yin Y, et al. The current situation on major depressive disorder in China: research on mechanisms and clinical practice. Neurosci Bull. 2016;32:389–97.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Fava M, Rush AJ, Thase ME, et al. 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry. 2005;7:106–13.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266–77.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Zhu M, Kaul S, Nandy P, et al. Model-based approach to characterize efavirenz autoinduction and concurrent enzyme induction with carbamazepine. Antimicrob Agents Chemother. 2009;2346–2353.Google Scholar
  10. 10.
    WHO China Office Fact Sheet. Depression. Last updated March 2017. Available from: Accessed 02 May 2018.
  11. 11.
    Wellbutrin XL® prescribing information. Bupropion hydrochloride extended-release tablets. Available from Accessed 02 May 2018.
  12. 12.
    Summary of Product Characteristics Wellbutrin XR. Available from Accessed 02 May 2018.
  13. 13.
    Jefferson JW, Pradko JF, Muir KT. Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. Clin Ther. 2005;27:1685–95.CrossRefPubMedGoogle Scholar
  14. 14.
    Hewett K, Gee MD, Krishen A, et al. Double-blind, placebo-controlled comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR. J Psychopharmacol. 2010;24:1209–16.CrossRefPubMedGoogle Scholar
  15. 15.
    Hewett K, Chrzanowski W, Schmitz M, et al. Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR. J Psychopharmacol. 2009;23:531–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Clayton AH, Croft HA, Horrigan JP, et al. Bupropion extended release compared with escitalopram: effects on sexual functioning and antidepressant efficacy in 2 randomized, double-blind, placebo-controlled studies. J Clin Psychiatry. 2006;67:736–46.CrossRefPubMedGoogle Scholar
  17. 17.
    Daviss WB, Perel JM, Birmaher B, et al. Steady-state clinical pharmacokinetics of bupropion extended-release in youths. J Am Acad Child Adolesc Psychiatry. 2006;45:1503–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Connarn JN, Flowers S, Kelly M, et al. Pharmacokinetics and pharmacogenomics of bupropion in three different formulations with different release kinetics in healthy human volunteers. AAPS J. 2017;19(5):1513–22.CrossRefPubMedGoogle Scholar
  19. 19.
    Li GF, Yu G, Liu HX, Zheng QS. Ethnic-specific in vitro-in vivo extrapolation and physiologically based pharmacokinetic approaches to predict cytochrome P450-mediated pharmacokinetics in the Chinese population: opportunities and challenges. Clin Pharmacokinet. 2014;53:197–202.CrossRefPubMedGoogle Scholar
  20. 20.
    Stengard J, Clark A, Weiss K, et al. Contributions of 18 additional DNA sequence variations in the gene encoding apolipoprotein E to explaining variation in quantitative measures of lipid metabolism. Am J Hum Genet. 2002;71:501–17.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lamba V, Lamba J, Yasuda K, et al. Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J Pharmacol Exp Ther. 2003;307:906–22.CrossRefPubMedGoogle Scholar
  22. 22.
  23. 23.
    GSK Clinical Study Register. Available from: Accessed 02 May 2018).
  24. 24.
    Park J, Vousden M, Brittain C, et al. Dose-related reduction in bupropion plasma concentrations by ritonavir. J Clin Pharmacol. 2010;50(10):1180–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Ma H, Zhang W, Yang X, et al. Effects of genetic polymorphisms of CYP2B6 on the pharmacokinetics of bupropion and hydroxybupropion in healthy Chinese subjects. Med Sci Monit. 2018;24:2158–63.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lei HP, Yu XY, Xie HT, et al. Effect of St. John’s wort supplementation on the pharmacokinetics of bupropion in healthy male Chinese volunteers. Xenobiotica. 2010;40(4):275–81.CrossRefPubMedGoogle Scholar
  27. 27.
    Qin WJ, Zhang W, Liu ZQ, et al. Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men. Br J Clin Pharmacol. 2012;74(6):999–1004.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.GlaxoSmithKline (China) R&D Company LimitedShanghaiChina
  2. 2.Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina
  3. 3.Shanghai Key Laboratory of Psychotic DisordersShanghaiChina

Personalised recommendations