European Journal of Clinical Pharmacology

, Volume 67, Issue 3, pp 253–260 | Cite as

Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients

  • Maud Berge
  • Romain Guillemain
  • David A. Trégouet
  • Catherine Amrein
  • Veronique Boussaud
  • Patrick Chevalier
  • Agnes Lillo-Lelouet
  • Christine Le Beller
  • Pierre Laurent-Puig
  • Philippe H. Beaune
  • Eliane M. Billaud
  • Marie-Anne Loriot



Voriconazole is widely used to treat invasive aspergillosis after lung transplantation. In cystic fibrosis patients, the interindividual variability in drug disposition complicates the optimal voriconazole dosing and increases the risk of toxicity. The objective of this retrospective study was to evaluate the influence of CYP2C19 genotype on voriconazole response in lung transplant patients with cystic fibrosis.


We retrospectively studied 24 Caucasian cystic fibrosis lung transplant recipients who received voriconazole. We analyzed the influence of CYP2C19 genotype (*2 and *17 alleles) on voriconazole exposure and maintenance dose and side effects.


Heterozygous carriers of the CYP2C19*2-deficient allele required lower maintenance doses (440 ± 107 mg/day) compared with wild-type and CYP2C19*17-allele carriers (633 ± 197 mg/day and 600 ± 193 mg/day, respectively, P < 0.05). The time to achieve the therapeutic range and the proportion of out-of-range concentrations were significantly higher in the CYP2C19*2 group (31.3% vs. 12.1% and 9.8% of above-range levels in the CYP2C19*1 and CYP2C19*17 groups, respectively) or CYP2C19*17 group (37.9% vs. 15.6% and 13% of below-range levels in the CYP2C19*1 and CYP2C19*2 groups, respectively) (P < 0.01). No relationship was found between voriconazole toxicity and CYP2C19 status.


In this frail population, voriconazole exposure is strongly influenced by CYP2C19 genotype, and determining the genotype before voriconazole initiation may help determine the initial dosing regimen that will promptly achieve therapeutic plasma levels without producing out-of-range levels.


Voriconazole Cystic fibrosis Lung transplantation CYP2C19 genotype 


Declaration of conflict of interest

The authors have no conflict of interest

Funding Sources

We thank the Pfizer laboratories for their financial support.


  1. 1.
    Herbrecht R, Denning DW, Patterson TF et al (2002) Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 347:408–415CrossRefPubMedGoogle Scholar
  2. 2.
    Walsh TJ, Anaissie EJ, Denning DW et al (2008) Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 46:327–360CrossRefPubMedGoogle Scholar
  3. 3.
    Smith J, Andes D (2008) Therapeutic drug monitoring of antifungals: pharmacokinetic and pharmacodynamic considerations. Ther Drug Monit 30:167–172CrossRefPubMedGoogle Scholar
  4. 4.
    Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O (2008) Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 46:201–211CrossRefPubMedGoogle Scholar
  5. 5.
    Kearns GL, Crom WR, Karlson KH Jr, Mallory GB Jr, Evans WE (1996) Hepatic drug clearance in patients with mild cystic fibrosis. Clin Pharmacol Ther 59:529–540CrossRefPubMedGoogle Scholar
  6. 6.
    Rey E, Treluyer JM, Pons G (1998) Drug disposition in cystic fibrosis. Clin Pharmacokinet 35:313–329CrossRefPubMedGoogle Scholar
  7. 7.
    Prandota J (1988) Clinical pharmacology of antibiotics and other drugs in cystic fibrosis. Drugs 35:542–578CrossRefPubMedGoogle Scholar
  8. 8.
    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
  9. 9.
    Kimura M, Ieiri I, Mamiya K, Urae A, Higuchi S (1998) Genetic polymorphism of cytochrome P450s, CYP2C19 and CYP2C9 in a Japanese population. Ther Drug Monit 20:243–247CrossRefPubMedGoogle Scholar
  10. 10.
    Sim SC, Risinger C, Dahl ML et al (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
  11. 11.
    Wang G, Lei HP, Li Z et al (2009) The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers. Eur J Clin Pharmacol 65:281–285CrossRefPubMedGoogle Scholar
  12. 12.
    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
  13. 13.
    Hafner V, Albermann N, Haefeli WE, Ebinger F (2008) Inhibition of voriconazole metabolism by chloramphenicol in an adolescent with central nervous system aspergillosis. Antimicrob Agents Chemother 52:4172–4174CrossRefPubMedGoogle Scholar
  14. 14.
    Liu P, Foster G, LaBadie RR, Gutierrez MJ, Sharma A (2008) Pharmacokinetic interaction between voriconazole and efavirenz at steady state in healthy male subjects. J Clin Pharmacol 48:73–84CrossRefPubMedGoogle Scholar
  15. 15.
    Scholz I, Oberwittler H, Riedel KD et al (2009) Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype. Br J Clin Pharmacol 68:906–915CrossRefPubMedGoogle Scholar
  16. 16.
    Johnson HJ, Han K, Capitano B et al (2010) Voriconazole pharmacokinetics in liver transplant recipients. Antimicrob Agents Chemother 54:852CrossRefPubMedGoogle Scholar
  17. 17.
    Karlsson MO, Lutsar I, Milligan PA (2009) Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies. Antimicrob Agents Chemother 53:935–944CrossRefPubMedGoogle Scholar
  18. 18.
    Geist MJ, Egerer G, Burhenne J, Mikus G (2006) Safety of voriconazole in a patient with CYP2C9*2/CYP2C9*2 genotype. Antimicrob Agents Chemother 50:3227–3228CrossRefPubMedGoogle Scholar
  19. 19.
    Eiden C, Peyrière H, Cociglio M et al (2007) Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database. Ann Pharmacother 41:755–763CrossRefPubMedGoogle Scholar
  20. 20.
    Cadena J, Levine DJ, Angel LF et al (2009) Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness. Am J Transplant 9:2085–2091CrossRefPubMedGoogle Scholar
  21. 21.
    Bégaud B, Evreux JC, Jouglard J, Lagier G (1985) Imputation of the unexpected or toxic effects of drugs. Actualization of the method used in France. Therapie 40:111–118PubMedGoogle Scholar
  22. 22.
    Pennick GJ, Clark M, Sutton DA, Rinaldi MG (2003) Development and validation of a high-performance liquid chromatography assay for voriconazole. Antimicrob Agents Chemother 47:2348–2350CrossRefPubMedGoogle Scholar
  23. 23.
    Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D (2002) Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 46:2546–2553CrossRefPubMedGoogle Scholar
  24. 24.
    Trifilio S, Ortiz R, Pennick G, Verma et al (2005) Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 35:509–513CrossRefPubMedGoogle Scholar
  25. 25.
    Berge M, Guillemain R, Boussaud V et al (2009) Voriconazole pharmacokinetic variability in cystic fibrosis lung transplant patients. Transpl Infect Dis 11:211–219CrossRefPubMedGoogle Scholar
  26. 26.
    Desta Z, Zhao X, Shin JG, Flockhart DA (2002) Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41:913–958CrossRefPubMedGoogle Scholar
  27. 27.
    Weiss J, Ten Hoevel MM, Burhenne J et al (2009) CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol 49:196–204CrossRefPubMedGoogle Scholar
  28. 28.
    Denning DW, Ribaud P, Milpied N et al (2002) Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 34:563–571CrossRefPubMedGoogle Scholar
  29. 29.
    Boyd AE, Modi S, Howard SJ, Moore CB, Keevil BG, Denning DW (2004) Adverse reactions to voriconazole. Clin Infect Dis 39:1241–1244CrossRefPubMedGoogle Scholar
  30. 30.
    Robinson M, Horn J (2003) Clinical pharmacology of proton pump inhibitors: what the practicing physician needs to know. Drugs 63:2739–2754CrossRefPubMedGoogle Scholar
  31. 31.
    Wood N, Tan K, Purkins L et al (2003) Effect of omeprazole on the steady-state pharmacokinetics of voriconazole. Br J Clin Pharmacol 56:56–61CrossRefPubMedGoogle Scholar
  32. 32.
    Levin MD, den Hollander JG, van der Holt B et al (2007) Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms. J Antimicrob Chemother 60:1104–1107CrossRefPubMedGoogle Scholar
  33. 33.
    Boussaud V, Daudet N, Billaud EM et al (2008) Neuromuscular painful disorders: a rare side effect of voriconazole in lung transplant patients under tacrolimus. J Heart Lung Transplant 27:229–232CrossRefPubMedGoogle Scholar
  34. 34.
    Imhof A, Schaer DJ, Schanz U, Schwarz U (2006) Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring. Swiss Med Wkly 136:739–774PubMedGoogle Scholar
  35. 35.
    Purkins L, Wood N, Greenhalgh K, Allen MJ, Oliver SD (2003) Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br J Clin Pharmacol 56:10–16CrossRefPubMedGoogle Scholar
  36. 36.
    Matsumoto K, Ikawa K, Abematsu K et al (2009) Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes. Int J Antimicrob Agents 34:91–94CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Maud Berge
    • 1
    • 2
  • Romain Guillemain
    • 3
  • David A. Trégouet
    • 4
  • Catherine Amrein
    • 3
  • Veronique Boussaud
    • 3
  • Patrick Chevalier
    • 3
  • Agnes Lillo-Lelouet
    • 2
  • Christine Le Beller
    • 2
  • Pierre Laurent-Puig
    • 1
    • 5
    • 6
  • Philippe H. Beaune
    • 1
    • 5
    • 6
  • Eliane M. Billaud
    • 1
    • 2
  • Marie-Anne Loriot
    • 1
    • 5
    • 6
    • 7
  1. 1.Université Paris DescartesParisFrance
  2. 2.Assistance-Publique des Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de PharmacologieParis Cedex 15France
  3. 3.Assistance-Publique des Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Chirurgie CardiovasculaireParis Cedex 15France
  4. 4.INSERM, UMR-S 937Université Pierre et Marie CurieParisFrance
  5. 5.INSERM UMR-S 775Bases moléculaires de la réponse aux xénobiotiquesParis Cedex 06France
  6. 6.Assistance-Publique des Hôpitaux de Paris, Hôpital Européen Georges PompidouService de Biochimie, Pharmacogénétique et Oncologie MoléculaireParis Cedex 15France
  7. 7.INSERM UMR-S 775Paris Cedex 06France

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