Curriculum Vitae

Optimising monoclonal antibodies therapy in inflammatory bowel diseases

Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders that affect the gastrointestinal tract. There are two main forms, Crohn’s disease (CD) and ulcerative colitis (UC), which primarily differ in symptoms and location of the inflammation. Immunosuppressive and anti-inflammatory small molecule agents are used as standard treatment for IBD. In many patients though the response to this treatment is absent, insufficient or fades over time. In these cases, monoclonal antibodies (mAbs) have demonstrated their value in IBD therapy.

Biologics have been developed with several different mechanisms of action. The first choice and the most extensively used mAb to treat IBD is infliximab (IFX), which works by inhibiting the pro-inflammatory cytokine tumour necrosis factor alpha. Some patients, however, lose their response to treatment with IFX over time, or suffer from adverse events. Vedolizumab (VDZ) and ustekinumab (UST) are two more recent immunosuppressive and anti-inflammatory mAbs also indicated for IBD patients, with different targets: α4β7 integrin or interleukin IL-12 and IL-23, respectively. Yet also response to therapy with VDZ and UST is still very different between individuals.

Variability among individuals in a population, in regards to drug exposure and treatment response, can be quantified using nonlinear mixed-effects (NLME) modelling. Moreover, with NLME modelling it is possible to also quantify the influence of patient-, disease- and therapy-specific characteristics (covariates) on the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug. NLME models can thus be a valuable tool to better understand and predict response to treatment, particularly on an individual level.

The focus of my research is on the optimisation and individualisation of mAbs therapy for IBD using the NLME modelling methodology. Through four projects, I will focus on different steps on the path towards individualised drug treatment, in particular in special subpopulations – From quantifying the variability in PK caused by different patient-specific factors, to implementations of new dosing strategies in clinical practice.

Two factors known to interfere with the efficacy of IFX drug therapy of IBD is increased disease activity and the development of anti-drug antibodies (ADAs). Project I is to create an overview of literature focused on the treatment with IFX for the subpopulations of IBD patients with moderate to acute severe UC (ASUC), and UC patients developing ADAs. The purpose is to investigate to what degree these factors have been quantified in NLME PK models of IFX, which will facilitate future efforts at adjusting treatments for these patient groups and highlight where further research is needed.

Similar to patients with ASUC, pregnant IBD patients are a subgroup requiring specific studies to assess and quantify possible changes in PK. In Project II, I will work towards treatment individualisation of VDZ in this specific subgroup of pregnant women with IBD. I will construct an NLME PK model enveloping the impact of trimester on drug exposure which subsequently can be used to learn which dose adjustments might be necessary during a pregnancy. These results will be compared to observed changes in IFX PK during pregnancy, which has been studied previously, also using NLME modelling.

NLME models can be used to guide dose adjustments in clinical practice, which is termed model-informed precision dosing (MIPD). However, before an NLME PK model can be used to guide individual dose adjustments, it must be known what plasma drug concentration is related to treatment success – often referred to as the PK/PD threshold. In Project III, I will derive the PK/PD threshold for VDZ.

Finally, a key requirement for successful MIPD is to base the procedure on a reliable NLME model. In Project IVa, I will compare and evaluate published NLME PK models for UST and VDZ in IBD patients, and using simulation-based techniques to identify the NLME model most suited for MIPD for both drugs. In Project IVb, the models chosen in Project IVa will be used together with previously established PK/PD thresholds to implement MIPD of UST and VDZ for IBD patients in a randomised, controlled clinical trial. The trial aims to compare MIPD to the current clinical practice in terms of both efficacy and costs – ultimately investigating the potential gains from implementing model-informed treatment individualisation of UST and VDZ in IBD patients.