Université Paris Descartes, Paris, France.
Eur J Clin Pharmacol. 2011 Mar;67(3):253-60. doi: 10.1007/s00228-010-0914-2. Epub 2010 Oct 31.
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 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.
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.
伏立康唑广泛用于肺移植后侵袭性曲霉菌病的治疗。在囊性纤维化患者中，药物处置的个体间差异使伏立康唑的最佳剂量复杂化，并增加了毒性的风险。本回顾性研究的目的是评估 CYP2C19 基因型对囊性纤维化肺移植患者伏立康唑反应的影响。
我们回顾性研究了 24 例接受伏立康唑治疗的白种人囊性纤维化肺移植受者。我们分析了 CYP2C19 基因型（2 和17 等位基因）对伏立康唑暴露和维持剂量以及副作用的影响。
CYP2C192 缺陷等位基因的杂合携带者需要较低的维持剂量（440 ± 107 mg/天），与野生型和 CYP2C1917 等位基因携带者（633 ± 197 mg/天和 600 ± 193 mg/天，分别，P<0.05）。达到治疗范围的时间和超出范围的浓度比例在 CYP2C192 组（分别为 31.3%比 CYP2C191 和 CYP2C1917 组的 12.1%和 9.8%，分别为高于范围水平）或 CYP2C1917 组（分别为 37.9%比 CYP2C191 和 CYP2C192 组的 15.6%和 13%，分别为低于范围水平）中显著更高（P<0.01）。在 CYP2C19 状态与伏立康唑毒性之间未发现相关性。
在这个脆弱的人群中，伏立康唑的暴露受 CYP2C19 基因型的强烈影响，在开始伏立康唑治疗之前确定基因型可能有助于确定初始剂量方案，该方案将迅速达到治疗血浆水平而不会产生超出范围的水平。
