Axis 1, Team11 | Pharmacokinetic/pharmacodynamic modeling for personalized treatment

Our methodology is focused on the analysis of pharmacokinetic and clinical-biological response data, through non-linear mixed-effects models in order to identify typical evolutionary patterns, quantify the variability within each population and to relate it to measurable characteristics such as age or comorbidities. In addition to solid training in PK/PD modeling methodology, the team members bring their clinical expertise in children and the elderly, as well as their expertise in the pharmacology of anti-infective and immunosuppressive drugs to ultimately allow a optimization and personalization of therapies.

PK/PD Modeling In Children

Infection is an important cause of neonatal morbidity and mortality. However, neonatal doses of antibiotics are extremely heterogeneous, nationally (Leroux 2015) and globally, and are often derived from exposures in adults or older children without adequate validation. Therefore, neonates are at risk of receiving suboptimal or toxic doses (Samardzic 2016). Our clinical objective in this project is to determine therapies and therapeutic targets suitable for newborns. We will combine PK/PD modeling of common antibiotic drugs in adults, children, and neonates with extrapolation methods to account for changes in model parameters with age, size, and maturation.

PK/PD Modeling In Chronic Diseases

The prognosis of patients undergoing transplantation has steadily improved over the past decades. Acute or chronic graft rejection is the main complication in patients after solid organ transplantation, and better characterization of patients at risk is needed. Our clinical objective in this theme is to study the fate of patients during long-term treatment with immunosuppressants such as tacrolimus. Methodological issues include modeling the longitudinal evolution of biomarkers and overall drug exposure measured by non-invasive micro-sampling approaches, and defining prognostic scores taking into account protein or metabolic profiles to identify populations at risk of rejection (Robertsen 2018). The final objective is to offer a personalized treatment taking into account all the parameters evaluated previously (Rayar 2018).

PK/PD Modeling In The Elderly

The elderly have frequent comorbidities and polypharmacy. They have physiological specificities that often do not allow a usual dosage of drugs. Aging is accompanied by a progressive impairment of the functional reserve of several organs, and changes in body composition that could affect the pharmacokinetics, response and safety of drugs (Klotz 2009). Guidelines for prescribing drugs are based on weak evidence, mainly due to the lack of specific studies in these populations. Modeling approaches could be useful to better characterize the covariates associated with PK/PD variability in order to provide useful prescribing tools for clinical practice. In addition, meta-analysis of individual patient data could help characterize the safety profile of drugs in this population (using the team's axis 2) which is little known. In this project, we will focus on two drugs of interest in this population, pregabalin and lidocaine.