Focus of research
Forschungslinie 2: Pharmacometric data analysis
“Pharmacokinetic and pharmacodynamic modelling of monoclonal antibodies” (working title)
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder that affects the gastro- intestinal tract. There are two main forms of the disease, Crohn’s disease and Ulcerative colitis, which differ in symptoms and location of the inflammation. In the gastrointestinal tract of the patients with IBD increased cytokine expression (e.g., tumor necrosis factor alpha, TNF) and elevated number of immune cells are present. The symptoms that patients most often experience include diarrhea, abdominal pain, malnutrition and fatigue.
Immunosuppressive and anti-inflammatory agents are used as standard treatment for IBD. However, in many patients the response to this treatment is absent or fades over time. As substitute for the standard therapy, certain monoclonal antibodies (mAbs) are employed. These antibodies are therapeutic proteins that bind with high specificity to their targets. Together with long half-lives, these characteristics make them promising pharmaceuticals.
One such mAb is infliximab, an IgG1 mAb against TNFα.
Due to lack of information necessary for successful treatment of IBD with mAbs, further studies are needed in order to complete the knowledge and develop an optimal dosing strategy. Immunogenicity and generation of anti-drug antibodies (ADAs) as well as their effect on pharmacokinetics and pharmacodynamics of mAbs are among the questions that require further investigation.
Mixed-effect modelling is a powerful approach for analysis of clinical data that are sparse, which is usually the case with mAbs related data. Moreover, this method enables evaluation
of the influence of patient specific characteristics (covariates) on the pharmacokinetics, pharmacodynamics and disease progression.
The focus of my PhD will be on the evaluation of population pharmacokinetic covariates and assessment of the effect of ADAs on the pharmacokinetics of mAbs. The results should provide us with guidance on how to use infliximab more efficiently as well as to broaden our knowledge about pharmacokinetics of infliximab.