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

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 CYP2C192-deficient allele required lower maintenance doses (440 ± 107 mg/day) compared with wild-type and CYP2C1917-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 CYP2C192 group (31.3% vs. 12.1% and 9.8% of above-range levels in the CYP2C191 and CYP2C1917 groups, respectively) or CYP2C1917 group (37.9% vs. 15.6% and 13% of below-range levels in the CYP2C191 and CYP2C192 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.