5PSQ-133 Discrepancies between observed voriconazole clearance and predicted according to CYP2C19 genetic polymorphism. Importance of therapeutic drug monitoring

<h3>Background and Importance</h3> Voriconazole requires therapeutic drug monitoring (TDM) due to its saturable hepatic metabolism and significant interindividual variability in plasma concentration influenced by genetic polymorphisms, hepatic dysfunction, C-reactive protein (CRP) levels, and drug interactions. <h3>Aim and Objectives</h3> This study aimed to assess whether the voriconazole dosing, adjusted through TDM to reach optimal blood levels, corresponded to that expected according to the patient’s CYP2C19 genotype, taking into account recent publications suggesting a dosing adjustment guided by the genetic polymorphism. <h3>Material and Methods</h3> A descriptive, observational, retrospective study was conducted including all patients treated with voriconazole between January 2022 and September 2024, with an average of 3.5 plasma concentration measurements and available CYP2C19 genotype data. CYP2C19 phenotyping was performed using CRP with the PHARM-CYP2C19 kit from Generi-Biotech to classify patients. Voriconazole serum concentrations were measured by Homogeneous Enzyme immunoassay. Dose adjustments based on TDM were obtained using a Bayesian model in the Abbott base-Pharmacokinetic System. The recommended therapeutic range was 1–5.5 µg/ml. Data related to drug interactions and CRP levels were collected. The TDM-guided dosing was compared to genetic polymorphism-based dosing using Zubiaur et al. 2021 as a reference. Clearance were considered discordant if they differed by 30% from the reference values. <h3>Results</h3> We included 46 patients, 71.74% male, with a mean age of 65.1 years (range:21–93). Two patients were classified as ultra-rapid metabolisers, 14 rapid, 17 normal, eight intermediate and five poor metabolisers. In 45.7% of patients, the TDM-adjusted dosing regimen was not as expected according to the patient’s phenotype. Twelve patients showed slower than expected elimination with the following mean clearance: six rapid metabolisers (Cl=1.15ml/min/kg), five normal (Cl=0.91ml/min/kg) and one ultra-rapid (Cl=0.92 ml/min/kg). In contrast, seven patients showed a higher-than-expected clearance: four normal (Cl=5.21ml/min/kg), one intermediate (Cl=9.15ml/min/kg) and two poor metabolisers (Cl=2.11ml/min/kg). Furthermore, drug interactions were observed with rifampicin (Cl=59.52ml/min/kg) and carbamazepine (Cl=10.27ml/min/kg) in a rapid and a normal metaboliser, respectively and elevated CRP levels &gt;120 mg/l in two rapid and one normal metaboliser as key factors contributing to these discrepancies. <h3>Conclusion and Relevance</h3> TDM is crucial for optimising plasma concentrations, as many patients had unexpected clearance based on their CYP2C19 genotype, though genotype remains an important covariate in voriconazole TDM. <h3>References and/or Acknowledgements</h3> DOI: 10.1007/s40262-020-00941-8 <h3>Conflict of Interest</h3> No conflict of interest