National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland.
Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
J Infect Dis. 2014 Jun 15;209(12):1941-8. doi: 10.1093/infdis/jiu017. Epub 2014 Jan 7.
Prospective evaluation of the antifungal drug, voriconazole, is needed to determine whether drug toxicity correlates with CYP2C19 genotype or serum concentrations of voriconazole or its metabolites.
We conducted a prospective study of 95 patients to determine voriconazole toxicity and its relationship to genotype and serum levels of voriconazole and its two metabolites. Efficacy was not evaluated because, in most cases, the drug was given for empirical or prophylactic therapy.
Hallucinations occurred in 16 patients (16.8%), visual changes in 17 (17.9%), photosensitivity in 10 (10.5%), and hepatotoxicity in 6 (6.3%). There was no correlation between photosensitivity or hepatotoxicity and levels of voriconazole or metabolites. Patients with hallucinations had higher average voriconazole levels (4.5 vs 2.5 μg/mL) but with extensive overlap. The recommended oral dose of 200 mg did not provide consistently detectable serum voriconazole levels in adults. CYP2C19 and CYP2C9 genotypes had a minor influence over levels, though the 4 patients homozygous for the 2C19*2 genotype had higher average levels for voriconazole (4.3 vs 2.5 μg/mL) and lower N-oxide levels (1.6 vs 2.5 μg/mL).
CYP2C19 and 2C9 genotypes were not major determinants of voriconazole metabolism. No toxic serum level of voriconazole or its metabolites could be identified.
需要对唑类抗真菌药物伏立康唑进行前瞻性评估，以确定药物毒性是否与 CYP2C19 基因型或伏立康唑或其代谢物的血清浓度相关。
我们进行了一项前瞻性研究，共纳入 95 例患者，以确定伏立康唑的毒性及其与基因型以及伏立康唑及其两种代谢物的血清水平之间的关系。由于大多数情况下药物是用于经验性或预防性治疗，因此未评估疗效。
16 例（16.8%）患者出现幻觉，17 例（17.9%）患者出现视觉改变，10 例（10.5%）患者出现光过敏，6 例（6.3%）患者出现肝毒性。光过敏或肝毒性与伏立康唑或代谢物的水平之间没有相关性。出现幻觉的患者平均伏立康唑水平较高（4.5μg/mL 比 2.5μg/mL），但存在广泛重叠。推荐的 200mg 口服剂量并不能为成年人提供始终可检测到的伏立康唑血清水平。CYP2C19 和 CYP2C9 基因型对水平有一定影响，但 4 例 2C19*2 纯合子患者的伏立康唑（4.3μg/mL 比 2.5μg/mL）和 N-氧化物水平（1.6μg/mL 比 2.5μg/mL）较低。
CYP2C19 和 2C9 基因型不是伏立康唑代谢的主要决定因素。未能确定伏立康唑或其代谢物的毒性血清水平。
