Clinical Impact of Cytochrome P450 2C19 Genotype on the Treatment of Invasive Aspergillosis under Routine Therapeutic Drug Monitoring of Voriconazole in a Korean Population
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Background: Genetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19 influence voriconazole pharmacokinetics. However,the impact of CYP2C19 genetic polymorphisms on the therapeutic efficacy and toxicity of voriconazole therapy are not well established. Materials and Methods: In this prospective observational study, we analyzed all consecutive adult patients with hematologic diseaseswho were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype androutine therapeutic drug monitoring of voriconazole were performed. The target range for voriconazole trough levels was 1−5.5 mg/L. Results: A total of 104 consecutive patients were enrolled, including 39 homozygous extensive metabolizers (EMs, 38%), 50 heterozygousextensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followedby HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantlyamong the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazolerelatedadverse events did not differ significantly among the 3 groups (P = 0.399, P = 0.412, P = 0.317, and P = 0.518, respectively). Conclusions: While none of the initial voriconazole trough levels in PMs was outside the target range, subtherapeutic initialtrough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either theclinical outcomes of IA or toxicity of voriconazole, further large-scale multicenter studies using clinical data from homogeneouspopulations are required.
Abstract
Background: Genetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19 influence voriconazole pharmacokinetics. However,the impact of CYP2C19 genetic polymorphisms on the therapeutic efficacy and toxicity of voriconazole therapy are not well established. Materials and Methods: In this prospective observational study, we analyzed all consecutive adult patients with hematologic diseaseswho were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype androutine therapeutic drug monitoring of voriconazole were performed. The target range for voriconazole trough levels was 1−5.5 mg/L. Results: A total of 104 consecutive patients were enrolled, including 39 homozygous extensive metabolizers (EMs, 38%), 50 heterozygousextensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followedby HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantlyamong the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazolerelatedadverse events did not differ significantly among the 3 groups (P = 0.399, P = 0.412, P = 0.317, and P = 0.518, respectively). Conclusions: While none of the initial voriconazole trough levels in PMs was outside the target range, subtherapeutic initialtrough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either theclinical outcomes of IA or toxicity of voriconazole, further large-scale multicenter studies using clinical data from homogeneouspopulations are required.
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