Infect Chemother.  2013 Dec;45(4):406-414. 10.3947/ic.2013.45.4.406.

Clinical Impact of Cytochrome P450 2C19 Genotype on the Treatment of Invasive Aspergillosis under Routine Therapeutic Drug Monitoring of Voriconazole in a Korean Population

• Kim SH
• Lee DG
• Kwon JC
• Lee HJ
• Cho SY
• Park C
• Kwon EY
• Park SH
• Choi SM
• Choi JH
• Yoo JH

• KMID: 2170444
• DOI: http://doi.org/10.3947/ic.2013.45.4.406

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 diseases who were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype and routine 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 heterozygous extensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2 mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followed by HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantly among the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazole-related adverse 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 initial trough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either the clinical outcomes of IA or toxicity of voriconazole, further large-scale multicenter studies using clinical data from homogeneous populations are required.

Keyword

Voriconazole; Therapeutic drug monitoring; CYP2C19; Invasive aspergillosis

MeSH Terms

Adult
Aspergillosis*
Cytochrome P-450 Enzyme System*
Cytochromes*
Drug Monitoring*
Genotype*
Hematologic Diseases
Humans
Mortality
Observational Study
Pharmacokinetics
Polymorphism, Genetic
Prospective Studies
Cytochrome P-450 Enzyme System
Cytochromes

Figure

• 

  Figure 1 Box plot of initial voriconazole trough levels according to CYP2C19 genotype (P = 0.232). Thick bar, median level; box, interquartile range; whiskers, minimum and maximum levels after the exclusion of outliers. EM, homozygous extensive metabolizer; HEM, heterozygous extensive metabolizer; PM, poor metabolizer.

• 

  Figure 2 Proportions of the ranges of initial (A) and overall (B) voriconazole trough levels according to CYP2C19 genotype. aP = 0.001, bP = 0.005, and cP = 0.037. EM, homozygous extensive metabolizer; HEM, heterozygous extensive metabolizer; PM, poor metabolizer.

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