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

f Voriconazole (VRC) plasma trough concentrations (C min ) 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 C min throughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRC C min (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 C min inter-and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRC C min (r ‫؍‬ 0.412, P < 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRC C min . Considering oral therapy, patients with a genetic score of <2 had higher initial VRC C min /D than patients with a genetic score of >2 (P ‫؍‬ 0.009). Subsequent VRC C min 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 C min 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 C min within the therapeutic range.

In Vitro Study of the Variable Effects of Proton Pump Inhibitors on Voriconazole

“…The in vitro inhibitory effects of esomeprazole on voriconazole appear to translate clinically as well. A post hoc analysis from a retrospective clinical study of voriconazole TDM revealed a statistically significant association between increased voriconazole concentrations and esomeprazole use (P Ͻ 0.0001) but not between increased voriconazole concentrations and pantoprazole or rabeprazole use (23). Pantoprazole appeared to have the smallest effect on voriconazole yield in our study, although a sizeable increase of 22% was still observed in pooled HLMs, and the effect of pantoprazole was similar to that of omeprazole.…”

“…As the product of an in vitro test, these results do not account for the complexity of organism-level physiology, and so it is difficult to correlate the concentrations of voriconazole and PPI used here with those that would be required to achieve similar effects in vivo. However, case studies indicate that the interaction between these drugs is both tolerated and measureable at clinically achievable concentrations (5,12,23), and the findings of further clinical studies to systematically determine these interactions would be informative when used in conjunction with the data from the present study.…”

“…Likewise, invasive soft tissue fungal infections have previously been described in immunocompromised patients (30)(31)(32) and have more recently been described to be an emerging problem in civilian and military trauma patients (33)(34)(35)(36). Several clinical studies evaluating voriconazole therapeutic drug monitoring and factors affecting plasma concentrations have reported an association between concomitant PPI use and elevated voriconazole concentrations (5,12,23). Furthermore, case reports of the occurrence of increased plasma voriconazole concentrations after coadministration of voriconazole with a PPI have also been reported; two of the reports were distinct, in that the studies involved the deliberate use of a PPI to boost voriconazole concentrations into the therapeutic range (19,20,37).…”

The influence of combination use of CYP450 inducers on the pharmacokinetics of voriconazole: a systematic review

“…However, different studies showed different results. Gautier et al 30 showed treatment with glucocorticoids had no impact on voriconazole C min (P = 0Á2) ( Table 3). Three studies (Eiden et al, Dolton et al, Naito et al) 28,29,31 reported that glucocorticoids slightly elevated the metabolism of voriconazole, although it did not affect the plasma exposure of voriconazole.…”

A genetic score combining CYP450 2C19 and 3A4 genotypes to predict voriconazole plasma exposure?

“…This SNP, the frequency of which varies from 6% to 13% in populations with European ancestry, was already identified as a determinant of several drug metabolisms [3]. We recently clearly demonstrated in recipients of allogeneic haematopoietic stem cell transplantation the impact of this SNP on VRC concentrations, since the presence of one *22 allele was associated with increased initial VRC trough concentrations, an effect independent of the CYP2C19 genotype [4]. Unfortunately, this study was not mentioned in the paper by Lamoureux et al [1], albeit it was the first to provide strong evidence for the impact of CYP3A4*22 on VRC exposure.…”