Early Serum Infliximab Levels in Severe Ulcerative Colitis.

The American Gastroenterology Association (AGA) recommends infliximab, a chimeric monoclonal
antibody to human tumor necrosis factor (anti-TNF), in the treatment of patients with
ulcerative colitis (UC) who don't achieve adequate clinical response despite treatment with
conventional therapy. Infliximab is an FDA approved therapy for ulcerative colitis based on
two large randomized trials, ACT I and ACT II. For patients who respond to induction
therapy, scheduled maintenance therapy has been demonstrated to be both durable and safe.
However, these trials did not include hospitalized patients.

Severe flares, or fulminant ulcerative colitis, remain highly morbid and potentially fatal
presentations of disease. Traditionally, hospitalized patients who failed high-dose
intravenous corticosteroid therapy require life-saving colectomy. Although the advent of
infliximab has presented an alternative rescue therapy, some patients with severe ulcerative
colitis are non-responders to anti-TNF induction therapy and proceed to colectomy. In the
ACT I and II trials, outpatients with moderate to severe ulcerative colitis were randomized
to placebo, 5mg/kg infliximab therapy, or 10mg/kg infliximab therapy. At 54 week follow-up,
patients receiving infliximab had a 41% reduced risk of colectomy compared to the placebo
group. Although infliximab at 5mg/kg was associated with a reduced risk of colectomy, only
the 10mg/kg infliximab dosing yielded a statistically significant risk reduction. There
were no differences in safety between the 5mg/kg and 10mg/kg infliximab groups; similar
rates of serious adverse events, infections, and infusion reactions were reported. Thus, at
our institution (University of California at San Francisco), it is our standard of care to
administer infliximab at 10mg/kg IV for patients hospitalized with severe ulcerative
colitis.

Dose escalation from 5mg/kg to 10mg/kg is routinely prescribed to recapture clinical
response in subsets of patients with inflammatory bowel disease who experience loss of
response during maintenance therapy and is supported in the FDA label for Crohn's disease.
Loss of response to infliximab maintenance therapy is a well-recognized phenomenon, and
there is abundant literature suggesting that durable and efficacious infliximab therapy is
dependent upon optimizing serum infliximab levels. Specifically, high serum infliximab
trough levels predict clinical response, but low serum trough levels and presence of
infliximab antibodies are associated with loss of response. However, serum infliximab
levels are not dependent upon drug dose and pharmacokinetics alone. Concurrent
immunomodulator use may reduce immunogenicity against monoclonal antibody therapies, and
more recently, there has been increased recognition of the importance of patient factors as
well. Specifically, variability in drug metabolism and clearance has been associated with
body-mass index, sex, and severity of inflammation - as measured by C-reactive protein,
serum albumin, and tumor necrosis factor alpha levels. It has been demonstrated that
patients with higher serum albumin levels maintain higher infliximab concentrations, lower
clearance, and longer drug half-lives than patients with lower serum albumin levels; and low
serum albumin correlates with poorer clinical response. Severe colonic disease is associated
with higher early fecal infliximab concentration, which is inversely associated with serum
infliximab levels and response to therapy. Moreover, high serum tumor necrosis factor alpha
levels prior to infliximab infusion predict poorer clinical outcomes and need for dose
escalation in patients with Crohn's disease and rheumatoid arthritis.

Patients hospitalized with severe ulcerative colitis can least afford suboptimal infliximab
therapy, but are at highest risk given their malnutrition and uncontrolled inflammation.
There is a growing trend towards the use of high dose of infliximab as the first line
therapy in these severe, hospitalized patients as they have just one infusion (dose) to
demonstrate clinical response before they are referred for colectomy. However, there is
currently no pharmacokinetic data to support this practice. There is only a small body of
literature that serum infliximab trough levels may predict clinical outcomes in acute
ulcerative colitis. To our knowledge, there are no studies regarding the use of early
infliximab levels - within the first 72 hours - to predict clinical response in the
vulnerable subset of patients hospitalized for severe ulcerative colitis.

We propose a pilot study investigating the treatment of severe ulcerative colitis with
high-dose infliximab (10mg/kg infusions), which is the standard of care at UCSF for severe,
hospitalized ulcerative colitis. This will be a prospective, multi-site study which will
consecutively enroll hospitalized ulcerative colitis patients meeting inclusion criteria
from anyone of four UCSF-affiliated hospitals. Per routine care, enrolled subjects will
undergo infectious work-up, receive intravenous corticosteroids in addition to supportive
care, and undergo evaluation by a Colorectal Surgeon. Subjects that are eligible for
anti-TNF therapy after routine screening will begin infliximab induction therapy on hospital
day 3 at 10mg/kg. We will perform standardized pre- and post-treatment assessments of
disease activity (Ulcerative Colitis Disease Activity Index - UCDAI), including acquisition
of biochemical and endoscopic data. We will measure serum levels of tumor necrosis factor
alpha, infliximab, and infliximab antibody throughout the course of treatment. The primary
outcome will be avoidance of colectomy. This study will be the first to our knowledge to
examine the empiric use of high-dose infliximab combined with early therapeutic drug
monitoring to guide the care of patients hospitalized with severe ulcerative colitis. Our
ultimate goal is to develop a rational approach to maximizing infliximab therapy in the
setting of severe ulcerative colitis to minimize and predict primary non-response to
infliximab induction therapy.

Aside from drawing infliximab and tumor necrosis factor alpha levels, all other procedures
and treatments provided to these patients are part of routine care for the patient with
severe ulcerative colitis. Routine care of the patient hospitalized with severe ulcerative
colitis is summarized in the following protocol:

On hospital days 1-2, hospitalized patients with severe ulcerative colitis undergo
diagnostic evaluation including bloodwork (complete blood count, C-reactive protein,
erythrocyte sedimentation rate, and serum albumin), infectious work-up (Clostridium
difficile, stool cultures, stool ova and parasites, cytomegalovirus), and standardized
assessment of disease activity (flexible sigmoidoscopy and calculation of UCDAI score).
Patients are started on corticosteroid therapy (Solumedrol 40mg intravenous daily), and
screened for eligibility for anti-tumor necrosis factor therapy (hepatitis B surface
antibody, hepatitis B core antibody, hepatitis B surface antigen, tuberculin skin test,
Quantiferon gold test, and chest radiograph). The Quantiferon gold tests are ordered for
inpatients. Intravenous antibiotics are given therapeutically in the event of documented
infection or clinical toxicity, but not prophylactically administered. Subcutaneous heparin
is administered for deep vein thrombosis prophylaxis per standard of care. On hospital day
3, a positive or negative response to intravenous corticosteroids is determined prior to
initiation of high-dose infliximab. Responders to medical therapy continue with an
infliximab induction regimen (week 0, 2, and 6 infusions). After completing the induction
regimen, patients undergo repeat flexible sigmoidoscopy and calculation of UCDAI score at
week 8.

Eligible study subjects will receive their first induction dose of infliximab (10mg/kg
intravenous infusion) on hospital day 3. A pre-infusion tumor necrosis factor alpha level
and an immediate post-infusion serum infliximab will be checked.

On hospital day 4, a serum tumor necrosis factor alpha and a 24 hour serum infliximab level
will be measured.

On hospital day 5, a serum tumor necrosis factor alpha and a 48 hour serum infliximab level
will be measured.

On hospital day 6, a serum tumor necrosis factor alpha and a 72 hour serum infliximab level
will be measured.

One week after initial infusion, a serum tumor necrosis factor alpha and a serum infliximab
level will be measured.

Two weeks after initial infusion, a serum tumor necrosis factor alpha and a serum infliximab
level will be measured.

Inclusion Criteria:

1. > 18 yrs.

2. Admitted with a primary diagnosis of ulcerative colitis.

3. Ulcerative colitis disease activity index score 6-12 (scale, 0-12).

4. Mayo endoscopic subscore of 2 or greater.

5. No prior treatment with infliximab.

6. Patients with prior or ongoing exposure to non-infliximab biologic therapies,
regardless of drug washout.

Exclusion Criteria:

1. < 18 yrs.

2. Other inflammatory bowel disease including Crohn's disease, indeterminate colitis,
and microscopic colitis.

3. Prior treatment with infliximab therapy.

4. Contraindication to anti-TNF therapy.