Pharmacokinetics of Micafungin in Patients of Intensive Care Units

Pharmacokinetics of Micafungin in Patients of Intensive Care Units

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.

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")