Invasive Aspergillosis Clinical Trial
Official title:
Influence of a Combined Pharmacogenetic Score on Through Plasma Voriconazole Concentrations in Haematological Patients
Hypothesis: A pharmacogenetic score integrating both CYP3A genotypes could be influence
initial trough voriconazole plasma concentrations and thus useful to adapt a priori
voriconazole dosing in order to get adequate voriconazole exposure as possible after starting
treatment.
Main Objective: To determine predictive value of a combined pharmacogenetic score on onset of
trough voriconazole plasma concentration inferior than lower therapeutic target.
Voriconazole (VRC), the gold-standard treatment of invasive aspergillosis is characterized by
variables and nonlinear pharmacokinetics, causing many under- or over-dosing. A link exist
between trough plasma concentrations (Cmin) of VRC and effectiveness but also its toxicity.
Thus the longitudinal therapeutic drug monitoring of VRC is now recommended with a
therapeutic range between 1 and 5 mg/L. The pharmacokinetic variability of VRC is in part
explained by its metabolism, mainly dependent on cytochrome P 450 (CYP), particularly
CYP2C19, 3A4, 3A5; all these CYP exhibiting genetic polymorphisms. The authors, recently
shown, and for the first time , in a retrospective study conducted in 29 patients allogeneic
hematopoietic stem cell that initial VRC Cmin adjusted the dose was not only influenced by
the route of administration but also by a pharmacogenetics score whose determination is to
assign each genotype CYP2C19 and CYP3A a score expressed in a arbitrary units.
The combined pharmacogenetic score was strongly correlated with the original Cmin (r= -0.748;
p = 0.002) and was the only independent predictor of initial Cmin (after adjusting the dose
and the route of administration). In addition, none of the patients having a genetic score <2
(ie metabolizing capacity of reduced VRC) did not show an initial Cmin below 1 mg/L, while
the initial Cmin was below this threshold efficiency in 47% of patients with a genetic score
>2. The aim of this new study is to confirm the impact of the pharmacogenetic score on the
initial VRC Cmin over a larger prospective cohort of 60 adult patients with
onco-hematological diseases.
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