Integrated pharmacokinetics of infliximab, adalimumab and golimumab in serum, tissue and faeces of patients with moderate to severe Ulcerative Colitis and Crohn's Colitis

The mechanism why some patients with Inflammatory Bowel Disease do not respond
to treatment with anti-tumor necrosis factor (TNF) agents such as infliximab
(IFX), is largely unknown. Recent studies performed by Brandse et
al.(Gastroenterology 2015) and Yarur et al (Gut 2014) investigated the role of
the luminal (feces) and mucosal (tissue) compartments in the pharmacokinetics
of IFX . It was shown that a significant proportion of IFX is lost through
leakage from the gut in to the feces, especially in the acute phase of the
disease, which led to impaired clinical outcome. As a consequence, patients
with severe inflammation need higher doses of anti-TNF to achieve clinical
effect. In order to fully understand the pharmacokinetics (PK) of three
different anti-TNF agents (IFX, adalimumab and golimumab) in patients with
moderate to severe Ulcerative Colitis or Crohn's colitis a mechanism -based PK
model needs to be developed consisting of multiple physiological compartments.
Therefore, we propose a PK study, focusing on anti-TNF and TNF levels in serum,
tissue and feces. These levels will be combined in an integrated PK model
quantifying the relationship between the dose and concentrations of anti-TNF in
the three compartments.

The primary aim of this study is to develop a physiologically-based PK model
for three different anti-TNF agents describing the relationship between dose
and concentration in three physiological compartments in patients with moderate
to severe colitis. Anti-TNF and TNF levels will be concomitantly measured in
serum, tissue and feces.

Cohort study

Participating will result in additional blood sampling and additional stool
sample collection (at 6 different time points). The first, baseline endoscopy
can be considered as standard care before starting treatment. After this
endoscopy, two additional endoscopies will be performed (day 14 and 42).
This study is considered to be a low-risk trial; all subjects will receive
anti-TNF treatment in accordance to standard care. The extra endoscopic
procedures are also considered low risk, with a risk of perforation risk of
0,001% and a bleeding risk of 1%