Clinical trial NCT06582186: Individualized First Maintenance Doses of Voriconazole Through a Multiparametric Algorithm
Official title: Individualization of First Maintenance Doses of Voriconazole Using a Multiparametric Algorithm in Hematology Patients: a Prospective Single-arm Interventional Study
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Aspergillosis Invasive
Fungal Infection
Hematologic Malignancy
Keywords: model-informed precision dosing
single-arm prospective interventional study
Simon design
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
First posted: 2024-09-03
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The goal of this interventional single-arm study is to evaluate the interest of a multiparametric algorithm for individualization of first voriconazole maintenance doses for improvement of initial voriconazole exposure in adult patients with haematological malignancies. The main objective it aims is to determine the percentage of patients with initial voriconazole trough concentrations in the therapeutic range after individualization of first maintenance doses.

Participants will benefited from individualization of first voriconazole maintenance doses through a previously developed and validated multiparametric algorithm (publication in progress) taking into account CYP2C19 genotype, C reactive protein level and age.

Detailed description: The currently recommended therapeutic drug monitoring of voriconazole has improved the efficacy of this treatment and reduced its adverse effects, especially for treatment and prophylaxis of invasive aspergillosis. However, dose adjustments made as part of this therapeutic drug monitoring only occur at the earliest 3 to 5 days after the initiation of treatment, whereas it is essential to achieve effective concentrations from the start of treatment. Simple a priori dose adjustment approaches based on CYP2C19 genotype have been shown to improve voriconazole exposure and treatment response. However other factors such as the patient\&#39;s inflammatory status or age also influence voriconazole exposure, suggesting that strategies for individualizing initial voriconazole doses could be improved by integrating all covariates influencing voriconazole pharmacokinetics. In this line, a previous multicenter and international study has developped and validated an algorithm for calculating the first maintenance doses integrating not only the CYP2C19 genotype, but also the inflammatory status, the patient\&#39;s age, and the presence (or not) of hematological malignancy. Here, the investigators propose to evaluate the interest of this multiparametric algorithm for improving initial exposure (within the first 4 days) to voriconazole in patients suffering from haematological malignancies.

Eligibility criteria: Inclusion Criteria:

* adult patient suffering from haematological malignancy
* followed in the clinical hematology department or in the hematology day hospital of the Grenoble Alps University Hospital
* consenting to carrying out CYP2C19 genotyping
* likely to start treatment with voriconazole (for curative or prophylactic purposes as part of care)
* having signed a written consent to participate
* affiliated to a social security system

Exclusion Criteria:

* comedication with strong inhibitors/inducers (valproic acid, phenytoin, carbamazepine, rifampicin)
* Subject during exclusion period from another study,
* Persons referred to in articles L1121-5 to L1121-8 of the CSP (corresponds to all protected persons: pregnant woman, parturient woman, breastfeeding mother, person deprived of liberty by judicial or administrative decision, persons subject to care psychiatric pursuant to articles L. 3212-1 and L. 3213-1 who do not fall under the provisions of article L. 1121-8, persons admitted to a health or social establishment for purposes other than research , minors, person subject to a legal protection measure or unable to express their consent)

Primary outcomes:
measure: Percentage of patients with initial plasma voriconazole trough concentration in the therapeutic range
timeFrame: Day 5 +/-2
Secondary outcomes:
measure: Frequency of initial plasma voriconazole trough concentrations above the therapeutic range
timeFrame: Day 5 +/-2
measure: Frequency of initial plasma voriconazole trough concentrations below the therapeutic range
timeFrame: Day 5 +/-2
measure: Voriconazole area under the curve (AUC0-12h) after the first maintenance dose individualized
timeFrame: Day 2
measure: Time to get the therapeutic range
timeFrame: through study completion, an average of 3 months
measure: Treatment outcome in patients curatively treated
timeFrame: At month 3 +/- 15 days
measure: Frequency of side effects
timeFrame: through study completion, an average of 3 months
measure: Percentage of patients with initial plasma voriconazole trough concentration in the therapeutic range
timeFrame: Day 5 +/-2
Other outcomes:
Locations:
city: Grenoble
country: France
facility: Gautier-Veyret
Study officials:
affiliation: Grenoble Alps University Hospital
name: Gautier-Veyret Elodie
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gautier-Veyret E, Thiebaut-Bertrand A, Roustit M, Bolcato L, Depeisses J, Schacherer M, Schummer G, Fonrose X, Stanke-Labesque F. Optimization of voriconazole therapy for treatment of invasive aspergillosis: Pharmacogenomics and inflammatory status need to be evaluated. Br J Clin Pharmacol. 2021 Jun;87(6):2534-2541. doi: 10.1111/bcp.14661. Epub 2020 Dec 13.
citation: Bolcato L, Khouri C, Veringa A, Alffenaar JWC, Yamada T, Naito T, Lamoureux F, Fonrose X, Stanke-Labesque F, Gautier-Veyret E. Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations: A Meta-Analysis of Individual Data. J Clin Med. 2021 May 13;10(10):2089. doi: 10.3390/jcm10102089.