title: 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: Voriconazole (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 VRC Cmin throughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRC Cmin (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 VRC Cmin inter- and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRC Cmin (r = 0.412, P < 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRC Cmin. Considering oral therapy, patients with a genetic score of <2 had higher initial VRC Cmin/D than patients with a genetic score of >2 (P = 0.009). Subsequent VRC Cmin remained influenced by the genetic score (P = 0.004) but were also affected by pump proton inhibitor comedication (P < 0.0001). The high variability of VRC Cmin in 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 individualize a priori the VRC dose and underlines the need for longitudinal therapeutic drug monitoring to adapt subsequent doses to maintain the VRC Cmin within the therapeutic range.
authors: Université Grenoble Alpes, Grenoble, France INSERM U1042, HP2, Grenoble, France Laboratoire de Pharmacologie-Toxicologie, Grenoble University Hospital, Grenoble, France EGautier@chu-grenoble.fr.
authors: Elodie
authors: E
authors: Gautier-Veyret
authors: Laboratoire de Pharmacologie-Toxicologie, Grenoble University Hospital, Grenoble, France.
authors: Xavier
authors: X
authors: Fonrose
authors: Laboratoire de Pharmacologie-Toxicologie, Grenoble University Hospital, Grenoble, France.
authors: Julia
authors: J
authors: Tonini
authors: Clinique d'Hématologie, Grenoble University Hospital, Grenoble, France TIMC-TheREx, UMR 5525, CNRS, La Tronche, France.
authors: Anne
authors: A
authors: Thiebaut-Bertrand
authors: Laboratoire de Pharmacologie-Toxicologie, Grenoble University Hospital, Grenoble, France.
authors: Mireille
authors: M
authors: Bartoli
authors: Département Scientifique de la Direction de la Recherche Clinique et des Innovations (DRCI), Grenoble University Hospital, Grenoble, France.
authors: Jean-Louis
authors: JL
authors: Quesada
authors: Clinique d'Hématologie, Grenoble University Hospital, Grenoble, France TIMC-TheREx, UMR 5525, CNRS, La Tronche, France.
authors: Claude-Eric
authors: CE
authors: Bulabois
authors: Université Grenoble Alpes, Grenoble, France Clinique d'Hématologie, Grenoble University Hospital, Grenoble, France TIMC-TheREx, UMR 5525, CNRS, La Tronche, France.
authors: Jean-Yves
authors: JY
authors: Cahn
authors: Université Grenoble Alpes, Grenoble, France INSERM U1042, HP2, Grenoble, France Laboratoire de Pharmacologie-Toxicologie, Grenoble University Hospital, Grenoble, France.
authors: Françoise
authors: F
authors: Stanke-Labesque
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001228:Aspergillosis / Q000150:complications / Q000188:drug therapy; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003967:Diarrhea / Q000382:microbiology; D004347:Drug Interactions; D005260:Female; D019337:Hematologic Neoplasms / Q000378:metabolism / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007206:Individuality; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D065819:Voriconazole / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D054328:Proton Pump Inhibitors; D003577:Cytochrome P-450 Enzyme System; D065819:Voriconazole
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