Modélisation pharmacocinétique de population de la Micafungine chez les patients hospitalisés en réanimation digestive au CHU de Montpellier
Year: 2025
Type: dissertation
Study design: Observational Study
Abstract: Invasive fungal infections (IFIs) are an increasingly serious public health concern, particularly in intensive care settings. The severity of the underlying pathophysiological conditions in these patients makes them more susceptible to such infections. Furthermore, rising resistance to antifungal agents, including echinocandins, highlights the need to optimize dosing strategies. So, we developed and validated a population pharmacokinetic (PKpop) model of Micafungin plasma concentrations in intensive care unit patients with suspected or proven IC. A nonlinear mixed-effects modelling approach was used to construct the PKpop model using Monolix. The impact of several covariates was evaluated. Then, a one-compartment model with linear elimination was identified, with a clearance (CL) of 0.86L/h (ωCL=27%) and a volume of distribution (Vd) of 18L (ωVd=13%) and body weight was identified as a significant covariate for both CL and Vd (βbody weight, CL: 0.63; βbody weight, Vd: 0.71). Moreover, total bilirubin concentration also significantly improved the model, with higher levels associated with reduced clearance (βbilirubin, CL: –0.097). This is the first population pharmacokinetic model developed in digestive ICU population, including 30% liver transplant recipients. Among the covariates that improved the model, body weight is commonly identified as a key factor explaining interindividual variability in CL and Vd contrary to total bilirubin. Indeed, in this study, bilirubin was significantly associated with decreased clearance. Given that Micafungin is metabolized and eliminated by the liver, it is plausible that impaired hepatic function, reflected by elevated total bilirubin, leads to reduced clearance. Moreover, the clearance value observed in our study population (CL=0.86L/h) is among the lowest reported in the literature, likely due to the high proportion of liver transplant recipients (30%) in our cohort. Further investigation will be conducted using Monte Carlo simulations to determine the optimal dosing regimen to achieve the PK/PD target.
Source: HAL
Author: Bendjilali-Sabiani, Jean-Joseph
Institution: Université de Montpellier
Language: French
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7111799757