Pharmacokinetics of Micafungin in Patients of Intensive Care Units

University Hospital, Limoges60 enrolled

Overview

Invasive fungal infections (IFIs) are a frequent cause of morbidity and mortality in high-risk patients, such as immunocompromised patients. Candida is currently the predominant fungal pathogen in these patient populations and is associated with significant morbidity and a high mortality. Micafungin (MCF) is a semisynthetic compound belonging to the new class of antifungal agents, the echinocandin lipopeptides, that has potent in vitro and experimental in vivo activity against a variety of pathogenic Candida species and Aspergillus species. Its applied indications are so the treatment and/or the prophylaxis of Candida and Aspergillus infections. MCF is currently licensed for the treatment of candidiasis at doses of either 100 or 150 mg a day. The efficacy of MCF is linked to the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC0-24/ MIC ratio). On one hand: \- It was demonstrated that 98% of invasive candidiasis patients with a MCF AUC/MIC ratio between 3 and 12 achieve microbiological clearance, as opposed to only 85% of those with an AUC/MIC ratio \< 3. In the case of infections by Candida parapsilosis, which exhibits drug MICs that are 50- to100-fold higher, 100% of patients with an AUC/MIC ratio \>285 achieve microbiological clearance, as opposed to 82% of those below that exposure level.(1) On the other hand: * It is well known that patients of intensive care units (ICU) are characterized by particular pharmacokinetic parameters with higher apparent volume of distribution (VC/F) and/or higher apparent systemic clearance (CL/F). In a population of healthy volunteers, it was observed that CL/F of MCF presents a high interpatient variability.(2) * Whether most ICUs patients achieve optimal AUC/MIC ratio thresholds at standard doses has not been investigated so far. In particular, lower AUCs might be reached in patients having the highest VC/F values. Such patients would then be at risk of therapy failure and would benefit from individualized-dosing strategies. In this context, the study of the pharmacokinetics of MCF in critically ill patients seems to be necessary.

Study Type

INTERVENTIONAL

Allocation

Purpose

OTHER

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Critically ill patients hospitalized in an ICU, with suspected or proven invasive fungal infections, for whom the decision has been made to start a treatment based on MCF. * Age \> 18 years. * Patients willing to give their written informed consent for their participation to the study. * Patients affiliated to the French social security system or equivalent. Exclusion Criteria: * Patient for whom a treatment based on MCF has already been started * Patient who have benefited from bone marrow transplantation * Age \< 18 years * Patient under legal protection * Patient deprived of liberty * Pregnant or breast-feeding woman or woman of childbearing potential without efficient contraception (based on declaration) * Patient with any altered mental status or any psychiatric condition that would interfere with the understanding of the study * Patient enrolled in another clinical trial testing drugs or therapeutic strategies (including the so-called "exclusion period")

Outcomes

Primary Outcomes

To describe micafungin concentrations over time,

The evaluation of the PK model performance will be based on its ability: * To describe micafungin concentrations over time, * To explain the sources of inter-individual PK variability. It will be done by the calculation of the bias between concentrations predicted using the model and observed concentrations.

Time frame: 3 weeks

Secondary Outcomes

To estimate the proportion of patients hospitalized in an ICU achieving the target AUC or AUC/MIC when receiving the recommended regimen

The estimation of the proportion of patients hospitalized in an ICU achieving the target AUC or AUC/MIC when receiving the recommended regimen will be based on the determination of exposure indices (AUC) and mycological characteristics (fungus and its MIC)