Experience of a Strategy Including CYP2C19 Preemptive Genotyping Followed by Therapeutic Drug Monitoring of Voriconazole in Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation

Abstract

Many factors have been described to contribute to voriconazole (VCZ) interpatient variability in plasma concentrations, especially CYP2C19 genetic variability. In 2014, Hicks et al. presented data describing the correlation between VCZ plasma concentrations and CYP2C19 diplotypes in immunocompromised pediatric patients and utilized pharmacokinetic modeling to extrapolate a more suitable VCZ dose for each CYP2C19 diplotype. In 2017, in our hospital, a clinical protocol was developed for individualization of VCZ in immunocompromised patients based on preemptive genotyping of CYP2C19 and dosing proposed by Hicks et al., Clinical Pharmacogenetics Implementation Consortium (CPIC) clinical guidelines, and routine therapeutic drug monitoring (TDM). We made a retrospective review of a cohort of 28 immunocompromised pediatric patients receiving VCZ according to our protocol. CYP2C19 gene molecular analysis was preemptively performed using PharmArray®. Plasma trough concentrations were measured by immunoassay analysis until target concentrations (1–5.5 μg/ml) were reached. Sixteen patients (57.14%) achieved VCZ trough target concentrations in the first measure after the initial dose based on PGx. This figure is similar to estimations made by Hicks et al. in their simulation (60%). Subdividing by phenotype, our genotyping and TDM-combined strategy allow us to achieve target concentrations during treatment/prophylaxis in 90% of the CYP2C19 Normal Metabolizers (NM)/Intermediate Metabolizers (IM) and 100% of the Rapid Metabolizers (RM) and Ultrarapid Metabolizers (UM) of our cohort. We recommended modifications of the initial dose in 29% (n = 8) of the patients. In RM ≥12 years old, an increase of the initial dose resulted in 50% of these patients achieving target concentrations in the first measure after initial dose adjustment based only on PGx information. Our experience highlights the need to improve VCZ dose predictions in children and the potential of preemptive genotyping and TDM to this aim. We are conducting a multicenter, randomized clinical trial in patients with risk of aspergillosis in order to evaluate the effectiveness and efficiency of VCZ individualization: VORIGENIPHARM (EudraCT: 2019-000376-41).

Therapeutic drug monitoring and CYP2C19 genotyping guide the application of voriconazole in children

“…Therefore, analysis of the CYP2C19 genotype may assist in clinical practice and improve patient outcomes. And it says the similar as García-García proved in 2021 (32).…”

Pharmacogenetic Expression of CYP2C19 in a Pediatric Population

“…Subtherapeutic concentrations were prevented in 83.8% of CYP2C19 rapid metabolizers receiving interventional dosing versus 46.2% receiving standard dosing [10]. One year later, Garcia-Garcia et al (2021) [11] reported analyses of 28 immunocompromised pediatric patients in whom preemptive CYP2C19 genotyping and therapeutic VCZ monitoring was performed. The final objective was to compare its results with the results obtained by Hicks et al and [12] used a PK model to optimize the voriconazole dosing regimen in children with severe disease.…”

Implementation of a pharmacogenetic panel‐based test for pharmacotherapy‐based supportive care in an adult oncology clinic

“…PGx‐guided therapy could guide the use of medications most likely to be effective, thereby reducing unnecessary medical complications and financial strain, as well as improve QoL. The use of PGx‐guided supportive care has been reported with opioids to help mitigate cancer‐related pain, prophylactic use of voriconazole in intermediate to high infection risk hematological malignancies, and ondansetron for chemotherapy‐induced nausea and vomiting (CINV) 19–25 . Institutions are increasingly implementing panel‐based PGx tests to preemptively guide medications with CPIC guidelines 26–28 .…”

“…The use of PGx‐guided supportive care has been reported with opioids to help mitigate cancer‐related pain, prophylactic use of voriconazole in intermediate to high infection risk hematological malignancies, and ondansetron for chemotherapy‐induced nausea and vomiting (CINV). 19 , 20 , 21 , 22 , 23 , 24 , 25 Institutions are increasingly implementing panel‐based PGx tests to preemptively guide medications with CPIC guidelines. 26 , 27 , 28 However, utilization of a panel‐based PGx approach to specifically guide supportive care medications in patients with cancer has not been widely described.…”