Influence of a Combined Pharmacogenetic Score on Through Plasma Voriconazole Concentrations in Haematological Patients (VORIGENE)
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|ClinicalTrials.gov Identifier: NCT03067350|
Recruitment Status : Completed
First Posted : March 1, 2017
Last Update Posted : February 18, 2019
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.
|Condition or disease|
|Invasive Aspergillosis Haematological Cancer Patients Voriconazole|
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.
|Study Type :||Observational|
|Actual Enrollment :||47 participants|
|Official Title:||Influence of a Combined Pharmacogenetic Score on Through Plasma Voriconazole Concentrations in Haematological Patients|
|Actual Study Start Date :||January 2015|
|Actual Primary Completion Date :||January 2019|
|Actual Study Completion Date :||January 2019|
- number of initial voriconazole trough plasma concentration in the therapeutic range (1-4mg/l) [ Time Frame: concentration measured between 5 to 10 days after voriconazole treatment initiation ]Initial voriconazole trough plasma concentration
- initial voriconazole trough plasma concentrations adjusted on the dose [ Time Frame: concentration measured between 5 to 10 days after voriconazole treatment initiation ]Initial voriconazole trough plasma concentration
- number of patients with therapeutic success [ Time Frame: 3 months after voriconazole therapy initiation ]treatment outcome determined 3 months after voriconazole initiation (failure, stable response, success)
- number of patients with adverse effects [ Time Frame: duration of voriconazole treatment (maximum length of follow-up : 3 months) ]adverse effects include neurological disorders such as visual disturbance and/or hallucinations and hepatotoxicity (evaluated by ALAT/ASAT, bilirubin and γ-GT levels),
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03067350
|University Hospital, Grenoble Alpes|
|Grenoble, France, 38043|
|Principal Investigator:||Elodie GAUTIER||University Hospital, Grenoble|