İnvaziv Fungal Enfeksiyon Nedeniyle Vorikonazol Tedavisi Alan Hematolojik Maligniteli Erişkin Hastalarda, CYP2C19 Polimorfizminin Vorikonazolün Güvenliliği Üzerine Etkisi

The Influence of CYP2C19 Polimorphism on The Safety of Voriconazole In Adult Patients with Hematologic Malignancy Receiving Voriconazole Treatment Due to an Invasive Fungal Infection Yeşim Tunçok1 , Özge Akçay1 , Boran Yavuz2 , Mualla Aylin Arıcı1 , Ayşe Gelal1 , Sema Alp Çavuş3 , Fatih Demirkan2 , Munir Pirmohamed4 , Mukaddes Gümüştekin1 1Department of Medical Pharmacology, Faculty of Medicine, Dokuz Eylul University, Izmir, Türkiye 2Department of Hematology, Faculty of Medicine, Dokuz Eylul University, Izmir, Türkiye 3Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Dokuz Eylul University, Izmir, Türkiye 4Department of Clinical Pharmacology, Faculty of Medicine, University of Liverpool, Liverpool, UK Objective: Invasive fungal infections (IFIs) remain a major cause of morbidity and mortality in immunocompromised patients, with rates approaching 50–60%. Voriconazole is a broad-spectrum antifungal widely used in the treatment and prophylaxis of invasive aspergillosis. Its metabolism is primarily mediated by the CYP2C19 enzyme, for which more than 30 variant alleles have been identified. The most frequent alleles are *2, *3, and *17; while *2 and *3 reduce enzyme activity, *17 increases it. Voriconazole’s narrow therapeutic index and interindividual variability may impact both efficacy and the risk of adverse drug reactions (ADRs). This study aimed to evaluate the frequency and severity of voriconazole-related ADRs and to investigate the impact of CYP2C19 polymorphisms on the safety profile of voriconazole. Methods: We conducted a single-center observational cohort study at Dokuz Eylül University Hospital, Hematology Department, between 2019-2023. Eligible patients were >=18 years old, hospitalized with hematologic malignancies, and received voriconazole therapy for proven/suspected IFI according to EORTC/MSG criteria. Clinical data and adverse events (AEs) were obtained from the electronic health record system. Voriconazole trough plasma concentrations were measured, and CYP2C19 genotyping was performed. Results: Twenty-five patients were included. Voriconazole levels were below the therapeutic range (1–5.5 μg/mL) in 2 patients and above in 6 patients. AEs were observed in 72% (n=18), most commonly hallucinations (n=7) and elevations in liver function tests (n=7). Pharmacogenetic analysis revealed that 7 patients are rapid metabolizers (*1/*17), 6 normal metabolizers (*1/*1, *17/*2), and 5 poor metabolizers (*1/*2). Conclusion: No statistically significant causal relationship was identified between AEs, voriconazole levels, and CYP2C19 polymorphisms. AEs were frequent in voriconazole-treated patients; however, further causality analyses are ongoing to clarify the relationship with voriconazole levels and CYP2C19 genotype. Due to limited number of patients in our study, there is a need for clinical studies with larger sample sizes. Keywords: Adverse Event, CYP2C19 Polymorphism, Invasive Fungal Infection, Voriconazole