Population Pharmacokinetics Approaches for the Optimization of Anti-infective Concentrations Among Hospitalized Patients

Patients with sepsis who receive inadequate AI regimen have a high risk of poor clinical outcomes. It is therefore critical to achieve adequate concentration of the AI as quickly as possible in these patients.

Pharmacokinetics (PK) describes the drug concentration-time courses in body fluids resulting from administration of a certain drug dose, pharmacodynamics (PD) the observed effect resulting from a certain drug concentration. The three PK/PD indices most commonly evaluated for AI are: the ratio of the maximal unbound drug concentration to the MIC (fCmax/MIC), the ratio of the area under the unbound drug concentration-time curve to the MIC (fAUC/MIC) or the percentage of a 24 h time period where the unbound drug concentration exceeds the MIC (fT.MIC). Dosing regimens are chosen to reach a target value of the main PK/PD index.

In hospitalized patients, a high between-subject variability is expected on PK parameters, related to the severity of the disease (sepsis, neutropenia, organ failure...), weight, age (geriatric patients, neonates...) and the co-administration of other medications leading to potential drug interactions. The PD variability is strongly influenced by the immune status, type of infection, inoculum size, comorbidities.

The optiPOP protocol aims to define a common framework to PK/PD studies conducted jointly by the Antimicrobial Stewardship Team, the Pharmacology department of Cochin hospital and within the APHP Centre hospital group.

These studies will use mathematical population pharmacokinetic modeling methodologies to investigate PK/PD parameters of various AI in a range of specific study populations (ICU, neutropenic patients…). The effects of covariates on PK and PD parameters will be investigated in order to better explain the between-subject variability and to ultimately suggest individualized dosage regimens.