SP4 - GUIDE-IBD

Model based dose recommendation

Pharmacokinetics (PK) of anti-TNF antibodies is known to display high inter-individual variability in IBD. Whereas a robust exposure-to-response relation has been established, detailed PK measurements are rarely employed in a clinical setting to guide dosing. Importantly, systematic differences between methods of drug level assessment (ELISA, MS) have been described. Several IBD-specific factors have been demonstrated to influence trough levels and elimination rates, which include e.g. inflammatory activity, anti-drug antibodies. Furthermore, little is known about PK behaviour of anti-TNF antibodies in special populations like elderly or organ (renal/hepatic) impaired patients. In this subproject, we will provide pharmacokinetic modelling techniques such as population pharmacokinetic modelling (popPK) and physiologically based pharmacokinetic modelling (PBPK) in our systems medicine study setup to guide a model-based individually optimized dosing recommendation. We will systematically compare ELISA and MS for determination of trough levels. We expect that this information
will help to optimize the induction of response and outcome of initial anti-TNF therapy.
Objectives
- To perform measurements of IFX trough levels (by ELISA and MS) and determine antidrug antibody concentrations for all patients of the study setup
- To develop a popPK model for IFX to calculate patient-individual IFX PK estimations and provide dosing recommendations based on IFX trough levels and relevant covariates (e.g. inflammatory activity, albumin) for the patients randomized into the “molecular medicine care” arm of the study.
- To develop a web-based and user-friendly interface for physicians to calculate the optimized IFX dose for the patients in the dose adjustment arm of the study.
- To develop a complementary PBPK model for IFX to predict IFX behaviour in special populations like elderly, renal or hepatic impaired patients.