European Journal of Clinical Pharmacology

, Volume 72, Issue 10, pp 1185–1193 | Cite as

Effect of cytochrome P450 2C19 polymorphisms on the clinical outcomes of voriconazole: a systematic review and meta-analysis

  • Xiaofei Li
  • Caiyuan Yu
  • Tiansheng Wang
  • Ken Chen
  • Suodi Zhai
  • Huilin TangEmail author



Genetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19, could influence voriconazole pharmacokinetics. The association between CYP2C19 polymorphisms and voriconazole clinical outcomes is not well established. The aim of this meta-analysis was to evaluate the effect of CYP2C19 polymorphisms on clinical outcomes in patients treated with voriconazole.


PubMed, EMBASE, CENTRAL,, and three Chinese databases were searched from their inception to January 2016 to identify eligible trials that reported voriconazole exposure and clinical outcomes of voriconazole according to CYP2C19 polymorphisms. Two reviewers independently reviewed the citations, extracted the data, and assessed the quality of the trials. The meta-analysis was performed using RevMan5.3.


A total of ten studies involving 598 patients were included. Compared with patients with extensive metabolizer (EM) phenotype, patients with poor metabolizer (PM) phenotype had significantly higher trough concentrations (MD, 1.22 mg/L; 95 % confidence interval (CI), 0.72–1.71; P < 0.0001). PM phenotype was also associated with a higher treatment success rate compared with EM phenotype (risk ratio (RR), 1.31; 95 % CI, 1.04–1.67; P = 0.02). However, there was no significant association between CYP2C19 polymorphisms and daily maintenance dose, overall adverse events, hepatotoxicity, and neurotoxicity.


Patients with CYP2C19 PM phenotype were associated with increased treatment success rate and trough concentrations as compared with those with EM phenotype. There was no significant association between CYP2C19 polymorphisms and either daily maintenance dose or adverse outcomes of voriconazole. However, large-scale, high-quality trials are still needed to confirm these findings.


CYP2C19 Polymorphism Voriconazole Meta-analysis 



The authors would like to thank Drs Dong and Bruggemann for providing the requested data. We also thank Dr Falcione Bonnie who provided language editing.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.


  1. 1.
    Jeu L, Piacenti FJ, Lyakhovetskiy AG, Fung HB (2003) Voriconazole. Clin Ther 25:1321–1381CrossRefPubMedGoogle Scholar
  2. 2.
    Hyland R, Jones BC, Smith DA (2003) Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos 31:540–547CrossRefPubMedGoogle Scholar
  3. 3.
    Dolton MJ, Mikus G, Weiss J, Ray JE, McLachlan AJ (2014) Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing. J Antimicrob Chemoth 69:1633–1641CrossRefGoogle Scholar
  4. 4.
    Jin H, Wang T, Falcione BA, Olsen KM, Chen K, Tang H, Hui J, Zhai S (2016) Trough concentration of voriconazole and its relationship with efficacy and safety: a systematic review and meta-analysis. J Antimicrob Chemother. doi: 10.1093/jac/dkw045 PubMedPubMedCentralGoogle Scholar
  5. 5.
    Karthaus M, Lehrnbecher T, Lipp HP, Kluge S, Buchheidt D (2015) Therapeutic drug monitoring in the treatment of invasive aspergillosis with voriconazole in cancer patients--an evidence-based approach. Ann Hematol 94:547–556CrossRefPubMedGoogle Scholar
  6. 6.
    de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA (1994) The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 269:15419–15422PubMedGoogle Scholar
  7. 7.
    Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79:103–113CrossRefPubMedGoogle Scholar
  8. 8.
    Pestka EL, Hale AM, Johnson BL, Lee JL, Poppe KA (2007) Cytochrome P450 testing for better psychiatric care. J Psychosoc Nurs Ment Health Serv 45:15–18PubMedGoogle Scholar
  9. 9.
    Bertilsson L (2007) Metabolism of antidepressant and neuroleptic drugs by cytochrome p450s: clinical and interethnic aspects. Clin Pharmacol Ther 82:606–609CrossRefPubMedGoogle Scholar
  10. 10.
    Desta Z, Zhao X, Shin JG, Flockhart DA (2002) Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41:913–958CrossRefPubMedGoogle Scholar
  11. 11.
    Owusu Obeng A, Egelund EF, Alsultan A, Peloquin CA, Johnson JA (2014) CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics? Pharmacotherapy 34:703–718CrossRefPubMedGoogle Scholar
  12. 12.
    Moriyama B, Kadri S, Henning SA, Danner RL, Walsh TJ, Penzak SR (2015) Therapeutic drug monitoring and genotypic screening in the clinical use of voriconazole. Curr Fungal Infect Rep 9:74–87CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang LJ, Tang HL, Duan JL (2011) Systematic review of influence on pharmacokinetics of voriconazole on CYP2C19 genetic polymorphisms. Chin J Clin Pharmacol 27:607–611Google Scholar
  14. 14.
    Li XF, Yu CY, Cheng Y, Niu TW, Chen K, Tang HL (2016) Effect of cytochrome P450 2C19 genotype on pharmacokinetics of vorivonazole in healthy volunteers: a systematic review and meta-analysis. Chin J Clin Pharmacol 32:267–269Google Scholar
  15. 15.
    Ikeda Y, Umemura K, Kondo K, Sekiguchi K, Miyoshi S, Nakashima M (2004) Pharmacokinetics of voriconazole and cytochrome P450 2C19 genetic status. Clin Pharmacol Ther 75:587–588CrossRefPubMedGoogle Scholar
  16. 16.
    Wang G, Lei HP, Li Z, Tan ZR, Guo D, Fan L, Chen Y, Hu DL, Wang D, Zhou HH (2009) The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers. Eur J Clin Pharmacol 65:281–285CrossRefPubMedGoogle Scholar
  17. 17.
    Weiss J, Ten Hoevel MM, Burhenne J, Walter-Sack I, Hoffmann MM, Rengelshausen J, Haefeli WE, Mikus G (2009) CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol 49:196–204CrossRefPubMedGoogle Scholar
  18. 18.
    Shi HY, Yan J, Zhu WH, Yang GP, Tan ZR, Wu WH, Zhou G, Chen XP, Ouyang DS (2010) Effects of erythromycin on voriconazole pharmacokinetics and association with CYP2C19 polymorphism. Eur J Clin Pharmacol 66:1131–1136CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hozo SP, Djulbegovic B, Hozo I (2005) Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 5:13CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Tang H, Yan Y, Wang T, Zhang T, Shi W, Fan R, Yao Y, Zhai S (2015) Effect of follicle-stimulating hormone receptor Asn680Ser polymorphism on the outcomes of controlled ovarian hyperstimulation: an updated meta-analysis of 16 cohort studies. J Assist Reprod Genet 32:1801–1810CrossRefPubMedGoogle Scholar
  21. 21.
    Matsumoto K, Ikawa K, Abematsu K, Fukunaga N, Nishida K, Fukamizu T, Shimodozono Y, Morikawa N, Takeda Y, Yamada K (2009) Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes. Int J Antimicrob Agents 34:91–94CrossRefPubMedGoogle Scholar
  22. 22.
    Bruggemann RJ, Blijlevens NM, Burger DM, Franke B, Troke PF, Donnelly JP (2010) Pharmacokinetics and safety of 14 days intravenous voriconazole in allogeneic haematopoietic stem cell transplant recipients. J Antimicrob Chemother 65:107–113CrossRefPubMedGoogle Scholar
  23. 23.
    Berge M, Guillemain R, Tregouet DA, Amrein C, Boussaud V, Chevalier P, Lillo-Lelouet A, Le Beller C, Laurent-Puig P, Beaune PH, Billaud EM, Loriot MA (2011) Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients. Eur J Clin Pharmacol 67:253–260CrossRefPubMedGoogle Scholar
  24. 24.
    Kim SH, Yim DS, Choi SM, Kwon JC, Han S, Lee DG, Park C, Kwon EY, Park SH, Choi JH, Yoo JH (2011) Voriconazole-related severe adverse events: clinical application of therapeutic drug monitoring in Korean patients. Int J Infect Dis 15:e753–e758CrossRefPubMedGoogle Scholar
  25. 25.
    Fu SS, Xiong X, Duan JL, Wang LJ, Liu Y, Jing HM, Zhai SD (2013) Voriconazole plasma concentration monitoring in patients. Chin J Clin Pharmacol 29:622–624Google Scholar
  26. 26.
    Kim SH, Lee DG, Kwon JC, Lee HJ, Cho SY, Park C, Kwon EY, Park SH, Choi SM, Choi JH, Yoo JH (2013) Clinical impact of cytochrome P450 2C19 genotype on the treatment of invasive aspergillosis under routine therapeutic drug monitoring of voriconazole in a Korean population. Infect Chemother 45:406–414CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wang T, Zhu H, Sun J, Cheng X, Xie J, Dong H, Chen L, Wang X, Xing J, Dong Y (2014) Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections. Int J Antimicrob Agents 44:436–442CrossRefPubMedGoogle Scholar
  28. 28.
    Zonios D, Yamazaki H, Murayama N, Natarajan V, Palmore T, Childs R, Skinner J, Bennett JE (2014) Voriconazole metabolism, toxicity, and the effect of cytochrome P450 2C19 genotype. J Infect Dis 209:1941–1948CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Liang FH, Meng DM, Xie H, Xiao XL, Lv BJ, Chen WY (2015) CYP2C19 gene polymorphism on plasma concentration of voriconazole in critically ill patients with invasive fungal infections. Chin J Hosp Pharm 35:1456–1461Google Scholar
  30. 30.
    Sumonrat C, Jantararoungtong T, Chitasombat MN, Puangpetch A, Prommas S, Dilokpattanamongkol P, Watcharananan SP, Sukasem C (2016) A prospective observational study of CYP2C19 polymorphisms and voriconazole plasma level in adult Thai patients with invasive aspergillosis. Drug Metab Pharmacokinet 31:117–122CrossRefGoogle Scholar
  31. 31.
    Ueda K, Nannya Y, Kumano K, Hangaishi A, Takahashi T, Imai Y, Kurokawa M (2009) Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders. Int J Hematol 89:592–599CrossRefPubMedGoogle Scholar
  32. 32.
    Levin MD, den Hollander JG, van der Holt B, Rijnders BJ, van Vliet M, Sonneveld P, van Schaik RH (2007) Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms. J Antimicrob Chemother 60:1104–1107CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Xiaofei Li
    • 1
    • 2
  • Caiyuan Yu
    • 1
    • 3
  • Tiansheng Wang
    • 4
  • Ken Chen
    • 1
  • Suodi Zhai
    • 1
  • Huilin Tang
    • 1
    Email author
  1. 1.Department of PharmacyPeking University Third HospitalBeijingChina
  2. 2.First Affiliated Hospital of Harbin Medical UniversityHarbinChina
  3. 3.The Open University of ChinaBeijingChina
  4. 4.Department of Pharmacy Administration and Clinical PharmacyPeking University Health Science CenterBeijingChina

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