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Correlation of CYP2C19 Phenotype With Voriconazole Plasma Concentration in Children

Narita, Atsushi MD*; Muramatsu, Hideki MD, PhD*; Sakaguchi, Hirotoshi MD*; Doisaki, Sayoko MD*; Tanaka, Makito MD, PhD*; Hama, Asahito MD, PhD*; Shimada, Akira MD, PhD*; Takahashi, Yoshiyuki MD, PhD*; Yoshida, Nao MD, PhD; Matsumoto, Kimikazu MD, PhD; Kato, Koji MD, PhD; Kudo, Kazuko MD, PhD; Furukawa-Hibi, Yoko PhD§; Yamada, Kiyofumi PhD§; Kojima, Seiji MD, PhD*

Journal of Pediatric Hematology/Oncology:
doi: 10.1097/MPH.0b013e3182880eaa
Online Articles: Clinical and Laboratory Observations
Abstract

Background: Voriconazole is a triazole antifungal agent with potent activity against a broad spectrum of pathogens, including Aspergillus and Candida species. In human adults, allelic polymorphisms of CYP2C19 are known to correlate with significant variation in voriconazole plasma concentration. Here, we report an analysis of CYP2C19 phenotype and voriconazole plasma concentrations in children.

Methods: This retrospective study included 37 children who had voriconazole plasma concentrations measured from May 2006 to June 2011. All had single-nucleotide polymorphisms that define the 3 major CYP2C19 alleles. Patients were classified as follows: normal metabolizers, intermediate metabolizers, poor metabolizers, or hypermetabolizers.

Results: The frequencies of the 3 CYP2C19 genetic polymorphisms were similar to those previously reported for Japanese adults. Trough plasma concentrations of voriconazole were significantly higher in the poor metabolizer and intermediate metabolizer groups compared with the normal metabolizer and hypermetabolizer groups (P=0.004). Two patients with high plasma concentrations experienced voriconazole-related severe adverse events (syndrome of inappropriate antidiuretic hormone secretion and cardiac toxicities).

Conclusions: The current study suggests that a significant association exists in children between the voriconazole plasma concentration and the CYP2C19 phenotype. Dose adjustment based on CYP2C19 phenotype may be useful during voriconazole therapy, especially for Japanese children, who as a group have a higher incidence of the poor metabolizer and intermediate metabolizer phenotypes.

Author Information

Departments of *Pediatrics

§Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine

Department of Pediatrics, Japanese Red Cross Nagoya First Hospital, Nagoya

Division of Hematology and Oncology, Shizuoka Children’s Hospital, Shizuoka, Japan

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A.N. and H.M.: designed and conducted the research, analyzed data, and wrote the paper; N.Y., K.M., K.K., and K.K.: treated patients; H.S., S.D., M.T., A.H., A.S., and Y.T.: conducted the research; and S.K.: designed the research, analyzed data, and wrote the paper.

The authors declare no conflict of interest.

Reprints: Seiji Kojima, MD, PhD, Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8650, Japan (e-mail: kojimas@med.nagoya-u.ac.jp).

Received June 28, 2012

Accepted January 15, 2013

© 2013 by Lippincott Williams & Wilkins.