Pharmacogenetics and beyond: variability of voriconazole plasma levels in a patient with primary immunodeficiency.

We report the case of a patient highly susceptible to invasive aspergillosis who received treatment with voriconazole (VRC). As part of therapeutic drug monitoring, VRC plasma trough concentrations were measured, showing undetectable levels (<0.16 µg/ml). Genotyping showed a heterozygous profile CYP2C19*1/*17, known to be associated with an ultrarapid-metabolism phenotype, contributing to the very low systemic exposure observed. Therefore, in this situation, the use of VRC treatment could be associated with therapeutic failure.

[1]  W. Haefeli,et al.  Modulators of Very Low Voriconazole Concentrations in Routine Therapeutic Drug Monitoring , 2011, Therapeutic drug monitoring.

[2]  S. Eymard-Duvernay,et al.  Pharmacokinetic variability of voriconazole and N-oxide voriconazole measured as therapeutic drug monitoring , 2010, Xenobiotica; the fate of foreign compounds in biological systems.

[3]  J. Ibrahim,et al.  In Vitro Hepatic Metabolism Explains Higher Clearance of Voriconazole in Children versus Adults: Role of CYP2C19 and Flavin-Containing Monooxygenase 3 , 2010, Drug Metabolism and Disposition.

[4]  Honghao Zhou,et al.  The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers , 2009, European Journal of Clinical Pharmacology.

[5]  W. Haefeli,et al.  CYP2C19 Genotype Is a Major Factor Contributing to the Highly Variable Pharmacokinetics of Voriconazole , 2009, Journal of clinical pharmacology.

[6]  D. Andes,et al.  Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications , 2008, Antimicrobial Agents and Chemotherapy.

[7]  M. Ingelman-Sundberg,et al.  Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. , 2008, British journal of clinical pharmacology.

[8]  Raoul Herbrecht,et al.  Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  Thierry Buclin,et al.  Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[10]  Edward T. Morgan,et al.  Gene-Specific Effects of Inflammatory Cytokines on Cytochrome P450 2C, 2B6 and 3A4 mRNA Levels in Human Hepatocytes , 2007, Drug Metabolism and Disposition.

[11]  A. Bura,et al.  Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. , 2006, Blood.

[12]  D. Andes,et al.  Voriconazole Therapeutic Drug Monitoring , 2006, Antimicrobial Agents and Chemotherapy.

[13]  A. Randolph,et al.  International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics* , 2005, Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

[14]  Marie M. Ahlström,et al.  Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[15]  D. Labuda,et al.  Dynamic allele-specific oligonucleotide hybridization on solid support. , 2004, Analytical biochemistry.

[16]  J. Goldstein,et al.  Identification of constitutive androstane receptor and glucocorticoid receptor binding sites in the CYP2C19 promoter. , 2003, Molecular pharmacology.

[17]  D. Alling,et al.  Itraconazole to prevent fungal infections in chronic granulomatous disease. , 2003, The New England journal of medicine.

[18]  J. Carcillo,et al.  Cytochrome P450 mediated-drug metabolism is reduced in children with sepsis-induced multiple organ failure , 2003, Intensive Care Medicine.

[19]  A. Fischer,et al.  Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000. , 2002, Blood.

[20]  M. Yamada,et al.  Successful Treatment with Methylprednisolone Pulse Therapy for a Life-Threatening Pulmonary Insufficiency in a Patient with Chronic Granulomatous Disease following Pulmonary Invasive Aspergillosis and Burkholderia cepacia Infection , 1999, Respiration.