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.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Variability of voriconazole plasma trough concentrations. (a) Serial voriconazole plasma trough concentrations determined in 33 post-AHSCT patients. All patients had at least 3 voriconazole concentration determinations, including several similar voriconazole concentrations for patients 7 and 23. The area shaded in gray represents the therapeutic range. (b) Relationships between voriconazole dose (expressed as mg per day) and plasma trough concentration for both routes of administration. Data are presented as interquartile range (boxes), data range (whiskers), and median (horizontal line). Numbers are indicated above boxes.

FIG 2

Influence of CYP450 polymorphisms on initial voriconazole plasma trough concentrations adjusted on the dose (VRC Cmin/D). (a and b) Influence of CYP2C19 phenotypes on initial VRC Cmin/D ratio obtained during VRC oral treatment (PO) (a) and on all initial VRC Cmin/D ratios (oral and i.v. [PO + IV]) (b). (c and d) Influence of CYP3A phenotypes on the initial VRC Cmin/D ratio obtained during VRC oral treatment (c) and on all initial VRC Cmin/D ratios (d). (e and f) Influence of the combined genetic score on the initial VRC Cmin/D ratio obtained during VRC oral treatment (e) and on all initial VRC Cmin/D ratios (f). Data are presented as interquartile range (boxes), data range (whiskers), and median (horizontal line). Only the significant P value obtained for the post hoc Bonferroni test (<0.0167) is shown. Abbreviations: VRC, voriconazole; CYP, cytochrome; PO, per os; IV, intravenous; URM, ultrarapid metabolizer; EM, extensive metabolizer; IM, intermediate metabolizer.

FIG 3

Influence of the genetic score on follow-up voriconazole plasma trough concentrations. Shown are the follow-up VRC Cmin (a) or Cmin/D ratio (b) according to the combined genetic score. Data are presented as interquartile range (boxes), data range (whiskers), and median (horizontal line), and only the significant P value obtained for the post hoc Bonferroni test (<0.0167 for three groups) is shown. (c) Temporal evolution of VRC trough concentrations throughout longitudinal TDM according to the combined genetic score. The area shaded in gray represents the therapeutic range. Solid circles, triangles, and squares represent the mean (± standard deviation) VRC Cmin for patients having genetic scores of <2, equal to 2, and >2, respectively. The asterisk indicates a P value of <0.05 for the Kruskal-Wallis test. Second, third, fourth, and fifth determinations of VRC Cmin were obtained after median periods of 7 (range, 2.8 to 28), 14 (range, 7.0 to 36), 35 (range, 11 to 59), and 53 (range, 20 to 87) days after the first determination.

FIG 4

Influence of pump proton inhibitor treatment on voriconazole plasma trough concentrations. Data are presented as interquartile range (boxes), data range (whiskers), and median (horizontal line).