Aspergillosis Invasive, Fungal Infection, Hematologic Malignancy
Conditions
Keywords
model-informed precision dosing, single-arm prospective interventional study, Simon design
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'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'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.
Interventions
DRUGIndividualization of first voriconazole maintenance doses
Individualization of first voriconazole maintenance doses
Sponsors
University Hospital, Grenoble
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of patients with initial plasma voriconazole trough concentration in the therapeutic range | Day 5 +/-2 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Voriconazole area under the curve (AUC0-12h) after the first maintenance dose individualized | Day 2 | — |
| Time to get the therapeutic range | through study completion, an average of 3 months | — |
| Treatment outcome in patients curatively treated | At month 3 +/- 15 days | — |
| Percentage of patients with initial plasma voriconazole trough concentration in the therapeutic range | Day 5 +/-2 | comparison with an historic cohort |
| Frequency of initial plasma voriconazole trough concentrations above the therapeutic range | Day 5 +/-2 | — |
| Frequency of initial plasma voriconazole trough concentrations below the therapeutic range | Day 5 +/-2 | — |
| Frequency of side effects | through study completion, an average of 3 months | — |
Countries
France
Contacts
Primary ContactGautier-Veyret Elodie, PharmD, PhD
Backup ContactThiebaut-bertrand Anne, MD
Outcome results
None listed