Students
Alix Démaris
Pharm.D. / Paris Descartes University, France
PharMetrX Research+ Program
PhD student year: 2019
University of PhD: Freie Universität Berlin
Supervisor: Prof. Charlotte Kloft
Co-Supervisor: Prof. Wilhelm Huisinga
Mentoring I-Partner: Merck
PhD Project
Optimising monoclonal antibodies therapy in inflammatory bowel diseases (working title)
Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders that affect the gastrointestinal tract. There are two main forms of the disease, Crohn’s disease (CD) and ulcerative colitis (UC), which primarily differ in symptoms and location of the inflammation. In the gastrointestinal tract of the patients with IBD increased cytokine expression (e.g., tumour necrosis factor alpha, TNFα) and an elevated number of immune cells are present. The symptoms that patients most often experience include diarrhoea, 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. Therefore, monoclonal antibodies (mAbs) can also be employed for IBD therapy. These antibodies are therapeutic proteins that bind with high specificity to their targets. Together with long half-lives, this characteristic makes them promising pharmaceuticals. The most widely used biologics in IBD are the TNFα inhibitors such as adalimumab, certolizumab, golimumab and infliximab, which are highly effective in the treatment of both UC and CD.
My research work will be focused on these therapies and the exploration of the loss of response associated with them. Loss of response to mAb therapy may be attributed to suboptimal drug exposure which in turn may be caused by the formation of antidrug antibodies. Moreover, response to therapy is highly variable between individuals. An optimal dosing strategy may reduce the development of loss of response in an individual and improve mAbs therapy for IBD patients. Further studies are needed in order to complete the knowledge in this area and support and improve optimal dosing strategies with mAbs in IBD patients.
One way to assess dosing strategies is pharmacokinetic (PK) and pharmacodynamic (PD) analysis of these mAbs. With this method, dosing strategy can be evaluated including its impact on exposure (PK) and response (PD). In my research work, two modelling approaches will be used for analysis of PK/PD data: Nonlinear mixed-effect (NLME) modelling and pharmacologically based pharmacokinetic (PBPK) modelling.
NLME modelling (also called population PK modelling) is a powerful approach for analysis of sparse clinical data, which is usually the case for mAbs related data. Moreover, these models can also quantify the interindividual and intraindividual variability in a population and enable evaluation of the influence of patient-, disease- and therapy-specific characteristics (covariates) on the PK, PD and disease progression. These covariates may explain part of the quantified variability and help to better understand the response variability to the treatment which is usually very high with mAbs.
PBPK modelling can also be used for analysis of PK and PD data. Those models are more mechanistic and allow the description of the drug´s PK/PD by taking into account different physiological and biological processes. PBPK/PD modelling can also be used to study special populations such as pregnant women in whom physiological changes occur over time.
NLME modelling and PBPK/PD modelling each bring its own set of information and can be built from different data sources. These approaches can thus be used complementarily to better understand the PK and PD of mAbs.
The focus of my research will be on the optimisation of mAbs therapy for IBD patients and pregnant women with IBD. My project will consist of characterisation of PK/PD of mAbs used in IBD using different modelling approached (i.e. population and PBPK modelling), including assessing the impacts of covariates and investigating special patient populations (i.e. pregnant IBD patients).
Publications
Please see the list of all publications and PhD theses.
Education
- 03/2019: Entering PharMetrX
- 02/2017-08/2018: Internship at Sanofi R&D, Alfortville, France
Topic: PopPK modelling of an ADC in early development and optimal design for a phase III trial and PopPK modelling of a mAb and determination of the active dose for children using allometric methods - 10/2017-08/2018: Master degree “Methods for therapeutics evaluation” at Paris Descartes and Paris Diderot Universities, France
- 02/2016-08/2017: Internship at Sanofi R&D, Montpellier, France
Topic: PBPK modelling in order to study the effect of polymorphism and DDI on drug exposure in healthy volunteers and pregnant women - 10/2016-08/2017: Master degree “Pharmacokinetics” at Paris Descartes University, France
- 04/2016-09/2016: Internship at Beaujon Hospital, Clichy, France, Pharmacology ward and Inserm, Paris, France, modelling unit UMR1137
Topic: PopPK modelling for the estimation of tacrolimus exposure in liver-transplanted patients in the early stage of their treatment. - 10/2015-04/2016: Externship at Beaujon Hospital, Clichy, France, Surgery and Hepatology Intensive Care Unit and Hepatology ward
- 09/2013-06/2015: Master degree “Physiology, Pharmacology and Toxicology” at Paris Descartes University, France