A reappraisal of measured voriconazole concentration based on plasma albumin concentration during therapeutic drug monitoring

Background: The unbound fraction of voriconazole can be elevated due to a decreased plasma albumin concentration. Given its nonlinear pharmacokinetic profile, this elevation can cause adverse effects even when the total voriconazole concentration is within the therapeutic window. This study investigated the factors affecting the plasma protein binding (PPB) of voriconazole and developed a method for the reappraisal of measured voriconazole concentration based on plasma albumin concentration. Methods: An observational retrospective study was performed on adult patients receiving voriconazole and therapeutic drug monitoring (TDM) from January 2019 to December 2020 at the First Affiliated Hospital of Wenzhou Medical University. The unbound voriconazole in plasma samples was separated using high-throughput equilibrium dialysis. Total voriconazole and unbound voriconazole concentrations were determined using liquid chromatography-tandem mass spectrometry. A Pearson correlation analysis was performed to analyze the correlations between voriconazole PPB and plasma albumin concentration, liver function, and concomitant medication. Results: A total of 193 cases with 470 voriconazole plasma samples were included. The median plasma concentration of voriconazole was 2.78 [1.56, 4.40] mg/L, median concentration of unbound voriconazole was 1.34 [0.61, 2.18] mg/L, and median binding rate of voriconazole PPB was 51.45% [45.53%, 57.89%]. The Pearson correlation analysis showed that voriconazole PPB was positively correlated with plasma albumin concentration (R = 0.664, P < 0.001). The current TDM window of voriconazole is defined as a total trough concentration within 1 to 4.5 mg/L, assuming voriconazole PPB of 50%. However, fluctuations in plasma albumin levels were found to have affected the unbound fraction of voriconazole, resulting in different responses or toxicity despite the measured voriconazole concentration being within the therapeutic window. Therefore, we developed a formula to amend the measured concentration of voriconazole to reflect the influence of a fluctuation in plasma albumin levels. Conclusion: Plasma albumin levels can affect voriconazole PPB and thus change the unbound fraction of voriconazole. An adjustment to the measured total voriconazole concentration based on plasma albumin concentration is needed during TDM. Keywords: Plasma albumin, voriconazole, therapeutic drug monitoring