Abstract
Abstract
Background: Voriconazole is a second-generation triazole antifungal with broad-spectrum activity against Aspergillosis, metabolized mainly by CYP2C19 in the liver. Despite the use of weight-based dosing, plasma voriconazole blood levels show inter-individual variability, which is attributed to many factors such as weight, age, food, drug interactions, and CYP2C19 polymorphism. Voriconazole metabolism in pediatrics has been reported to be profoundly impacted by CYP2C19 genotypes. Aim: To evaluate the frequencies of CYP2C19 variant alleles (*2, *3, and *17), genotypes, and phenotypes in Egyptian pediatric cancer patients and to investigate the correlation between CYP2C19 genetic variability and other factors with voriconazole plasma levels. Methods: This study was conducted on 100 pediatric cancer patients with probable fungal infection treated with voriconazole. DNA was extracted from blood samples and analyzed by the TaqMan SNP genotyping assay. Identified genotypes were classified accordingly into various predicted phenotypes. Results: Voriconazole plasma levels widely varied, with only 49.5% reaching therapeutic levels. Frequencies of CYP2C19*2 and *17 allelic variants were 10.6 and 18.3%, respectively, while allele *3 was not detected in the study population. A significant correlation was found between plasma levels and CYP2C19 phenotypes: ultra-rapid metabolizers had significantly lower plasma levels (P=0.003) relative to the extensive metabolizer genotype. Conclusion: Determination of CYP2C19 genotype at initiation of therapy, followed by drug monitoring, would serve as a valuable tool for the optimization of voriconazole therapy for pediatric cancer patients. It would also be an essential step in the advancement of precision medicine to optimize therapeutic efficacy and minimize toxicity.
Citation Format: Dina Saeed, Lobna Shalaby, Mohamed Nagy, Ahmed ElZeiny, Tarek M. Mostafa, Marwa T. ElRakaiby, Mohammed M. Nooh, Alaa El-Haddad, Maggie Abbassi, Ramy K. Aziz. Investigating the effect of pharmacogenetic variations on voriconazole levels in pediatric cancer patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B19. doi:10.1158/1535-7163.TARG-19-LB-B19