Variability of Voriconazole Plasma Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Cytochrome P450 Polymorphisms and Comedications on Initial and Subsequent Trough Levels

Abstract

ABSTRACTVoriconazole (VRC) plasma trough concentrations (Cmin) are highly variable, and this could affect treatment efficacy and safety in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). We aimed to describe the intra- and interindividual variation of VRCCminthroughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRCCmin(n= 308) of 33 AHSCT patients were retrospectively collected. Cytochrome P450 (CYP450) genotypes of CYP2C19, CYP3A4, and CYP3A5 patients were retrospectively determined before allografting, and a combined genetic score was calculated for each patient. The higher the genetic score, the faster the metabolism of the patient. The VRCCmininter- and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRCCmin(r= 0.412,P< 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRCCmin. Considering oral therapy, patients with a genetic score of <2 had higher initial VRCCmin/Dthan patients with a genetic score of >2 (P= 0.009). Subsequent VRCCminremained influenced by the genetic score (P= 0.004) but were also affected by pump proton inhibitor comedication (P< 0.0001). The high variability of VRCCminin AHSCT patients is partially explained by the route of administration, treatment with pump proton inhibitors, and the combined genetic score. This study suggests the interest in combined genetic score determination to individualizea priorithe VRC dose and underlines the need for longitudinal therapeutic drug monitoring to adapt subsequent doses to maintain the VRCCminwithin the therapeutic range.