Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients
Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients
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DOI：
10.1007/s00228-010-0914-2
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发表时间：
2011-03-01
影响因子：
2.9
通讯作者：
Loriot, Marie-Anne
中科院分区：
文献类型：
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作者：
Berge, Maud;Guillemain, Romain;Loriot, Marie-Anne
伏立康唑广泛用于治疗肺移植后侵袭性曲霉病。在囊性纤维化患者中，药物分布的个体间差异使伏立康唑的最佳剂量复杂化，并增加了毒性风险。本回顾性研究的目的是评估CYP 2C 19基因型对肺移植合并囊性纤维化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人囊性纤维化肺移植患者。我们分析了CYP 2C 19基因型（*2和 *17等位基因）对伏立康唑暴露、维持剂量和副作用的影响。CYP 2C 19 *2缺陷等位基因的杂合子携带者需要较低的维持剂量与野生型和CYP 2C 19 *17等位基因携带者（分别为633 +/- 197 mg/天和600 +/- 193 mg/天，P < 0.05）相比，CYP 2C 19 *17等位基因携带者（440 +/- 107 mg/天）。CYP 2C 19 *2组达到治疗范围的时间和超出范围浓度的比例显着较高（CYP 2C 19 *1和CYP 2C 19 *17组中高于范围水平的比例分别为31.3%、12.1%和9.8%，CYP 2C 19 *17组（37.9%）和CYP 2C 19 *1组（15.6%）及CYP 2C 19 *2组（13%）低于正常范围（P < 0.01）。伏立康唑毒性与CYP 2C 19状态之间没有发现相关性。在这个虚弱的人群中，伏立康唑暴露受CYP 2C 19基因型的强烈影响，在伏立康唑开始治疗前确定基因型可能有助于确定初始给药方案，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。
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.