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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
Pharmacogenetics

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Voriconazole Cystic fibrosis Lung transplantation CYP2C19 genotype 

Notes

Declaration of conflict of interest

The authors have no conflict of interest

Funding Sources

We thank the Pfizer laboratories for their financial support.

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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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