Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
Not provided
Not provided
Not provided
Not provided
Not provided
| Measure | Description | Time Frame |
|---|---|---|
| number of initial voriconazole trough plasma concentration in the therapeutic range (1-4mg/l) | Initial voriconazole trough plasma concentration | concentration measured between 5 to 10 days after voriconazole treatment initiation |
| Measure | Description | Time Frame |
|---|---|---|
| initial voriconazole trough plasma concentrations adjusted on the dose | Initial voriconazole trough plasma concentration | concentration measured between 5 to 10 days after voriconazole treatment initiation |
| number of patients with therapeutic success |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
patients suffering from haematological cancer Followed at the hematolofic clinic of Grenoble University Hospital Starting treatment by voriconazole whatever the route of administration
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Elodie GAUTIER | University Hospital, Grenoble | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital, Grenoble Alpes | Grenoble | 38043 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25645831 | Background | Gautier-Veyret E, Fonrose X, Tonini J, Thiebaut-Bertrand A, Bartoli M, Quesada JL, Bulabois CE, Cahn JY, Stanke-Labesque F. Variability of voriconazole plasma concentrations after allogeneic hematopoietic stem cell transplantation: impact of cytochrome p450 polymorphisms and comedications on initial and subsequent trough levels. Antimicrob Agents Chemother. 2015 Apr;59(4):2305-14. doi: 10.1128/AAC.04838-14. Epub 2015 Feb 2. | |
| 27318623 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
treatment outcome determined 3 months after voriconazole initiation (failure, stable response, success)
| 3 months after voriconazole therapy initiation |
| number of patients with adverse effects | adverse effects include neurological disorders such as visual disturbance and/or hallucinations and hepatotoxicity (evaluated by ALAT/ASAT, bilirubin and γ-GT levels), | duration of voriconazole treatment (maximum length of follow-up : 3 months) |
| Background |
| Gautier-Veyret E, Fonrose X, Stanke-Labesque F. A genetic score combining CYP450 2C19 and 3A4 genotypes to predict voriconazole plasma exposure? Int J Antimicrob Agents. 2016 Aug;48(2):221-2. doi: 10.1016/j.ijantimicag.2016.05.002. Epub 2016 Jun 7. No abstract available. |
| 26384041 | Background | Tonini J, Bailly S, Gautier-Veyret E, Wambergue C, Pelloux H, Thiebaut-Bertrand A, Cornet M, Stanke-Labesque F, Maubon D. Contribution of a Simple Bioassay in Effective Therapeutic Drug Monitoring of Posaconazole and Voriconazole. Ther Drug Monit. 2015 Oct;37(5):685-8. doi: 10.1097/FTD.0000000000000199. |
| 22850515 | Background | Tonini J, Thiebaut A, Jourdil JF, Berruyer AS, Bulabois CE, Cahn JY, Stanke-Labesque F. Therapeutic drug monitoring of posaconazole in allogeneic hematopoietic stem cell transplantation patients who develop gastrointestinal graft-versus-host disease. Antimicrob Agents Chemother. 2012 Oct;56(10):5247-52. doi: 10.1128/AAC.00815-12. Epub 2012 Jul 30. |
| 23384531 | Background | Jourdil JF, Tonini J, Stanke-Labesque F. Simultaneous quantitation of azole antifungals, antibiotics, imatinib, and raltegravir in human plasma by two-dimensional high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2013 Mar 1;919-920:1-9. doi: 10.1016/j.jchromb.2012.12.028. Epub 2013 Jan 9. |