Influence of a Combined Pharmacogenetic Score on Through Plasma Voriconazole Concentrations in Haematological Patients

Invasive Aspergillosis Clinical Trial

— VORIGENE  

Official title:

Influence of a Combined Pharmacogenetic Score on Through Plasma Voriconazole Concentrations in Haematological Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03067350
• Other study ID #: 38RC15.168
• Status: Completed
• Start date: January 2015
• Est. completion date: January 2019

Study information

• Verified date: February 2019
• Source: University Hospital, Grenoble
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: January 2019
• Est. primary completion date: January 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• patients suffering from haematological cancer

Exclusion Criteria:

• less than 18-years old

Related Conditions & MeSH terms

• Aspergillosis
• Haematological Cancer Patients
• Invasive Aspergillosis
• Voriconazole

Locations

Country	Name	City	State
France	University Hospital, Grenoble Alpes	Grenoble

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Grenoble

Country where clinical trial is conducted

France, 

References & Publications (5)

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. — View Citation

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. — View Citation

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. — View Citation

Tonini J, Bailly S, Gautier-Veyret E, Wambergue C, Pelloux H, Thiébaut-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. — View Citation

Tonini J, Thiébaut 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Secondary	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
Secondary	number of patients with therapeutic success	treatment outcome determined 3 months after voriconazole initiation (failure, stable response, success)	3 months after voriconazole therapy initiation
Secondary	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 ?-GT levels),	duration of voriconazole treatment (maximum length of follow-up : 3 months)