Abstract
Invasive fungal infections (IFIs) are the most frequent cause of morbidity and mortality in immunocompromised children. Voriconazole is the first-line antifungal choice in the treatment of IFIs like aspergillosis. Voriconazole pharmacokinetics vary widely among patients and voriconazole is metabolized mainly in the liver by the CYP2C19 enzyme, which is highly polymorphic. The CYP2C19*17 allele is characterized by the presence of four single nucleotide polymorphisms expressing an ultra-rapid enzyme phenotype with an accelerated voriconazole metabolism, is associated with low (sub-therapeutic) plasma levels in patients treated with the standard dose. Considering that in our center a high percentage of children have sub-therapeutic levels of voriconazole when treated with standard doses, we sought to determine the frequency of the CYP2C19*17 polymorphism (rs12248560) in a Chilean population and determine the association between voriconazole concentrations and the rs12248560 variant in immunocompromised children. First, we evaluated the frequency of the rs12248560 variant in a group of 232 healthy Chilean children, and we found that 180 children (77.6%) were non-carriers of the rs12248560 variant, 49 children (21.1%) were heterozygous carriers for rs12248560 variant and only 3 children (1.3%) were homozygous carriers for rs12248560 variant, obtaining an allelic frequency of 12% for variant in a Chilean population. To determine the association between voriconazole concentrations and the rs12248560 variant, we analyzed voriconazole plasma concentrations in a second group of 33 children treated with voriconazole. In these patients, carriers of the rs12248560 variant presented significantly lower voriconazole plasma concentrations than non-carriers (p = 0,011). In this study, we show the presence of the rs12248560 variant in a Chilean population and its accelerating effect on the pharmacokinetics of voriconazole in pediatric patients. From these data, it would be advisable to consider the variant of the patient prior to calculating the dosage of voriconazole.
Highlights
Pediatric patients diagnosed with hemato-oncological diseases or who have had a solid organ transplant must undergo prolonged periods of chemotherapy and immunosuppressive therapy, which makes these patients susceptible to invasive fungal infections (IFIs)[1,2]
Voriconazole is metabolized in the liver, mainly by two cytochrome P450 enzymes (CYP), CYP2C19 and CYP3A4, and flavin-containing monooxygenase 3 (FMO3)[7,8] converting it to N-oxide voriconazole
The rs12248560 variant is associated with an ultra-rapid metabolizer phenotype of enzyme CYP2C19, which translates into a faster elimination of the drug in patients who receive treatment with standard doses of voriconazole with the consequent risk of therapeutic failure, making dosage corrections necessary[14,15,16]
Summary
Pediatric patients diagnosed with hemato-oncological diseases or who have had a solid organ transplant must undergo prolonged periods of chemotherapy and immunosuppressive therapy, which makes these patients susceptible to invasive fungal infections (IFIs)[1,2]. These infections are caused by the colonization of pathogens of the genus Aspergillus and Candida and are an important cause of morbimortality in pediatric patients. Voriconazole is a broad-spectrum anti-fungal drug that belongs to the family of second-generation triazoles It is used as a first-line treatment for IFIs, characterized by a high inter- and intra-patient pharmacokinetic variability. The aim of this work was to describe the frequency of rs12248560 variant in a Chilean population and to study its association with the pharmacokinetics of voriconazole in pediatric patients
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