Clinical pharmacology: anti-TNF therapy in the treatment of inflammatory bowel diseases

1. Anti-tumor necrosis
factor therapy
Domina Petric, MD
Inflammatory bowel disease (IBD) pharmacology

2. Surgery
Natalizumab
Cyclosporine
TNF antagonists
Iv. corticosteroids
TNF antagonists
Oral corticosteroids
Methotrexate
Azathioprine
6-Mercaptopurine
Budesonide (ileitis)
Topical corticosteroids (proctitis)
Antibiotics
5-Aminosalicylates
Severe disease
Moderate disease
Mild disease
Refractory
Responsive

3. Pharmacokinetics
A dysregulation of the helper T cell
type 1 (TH1) response and regulatory
T cells (Tregs) is present in IBD.
One of the key proinflammatory
cytokines in IBD is tumor necrosis
factor (TNF).

4. TNF is produced by:
innate immune system
(dendritic cells, macrophages)
adaptive immune system
(especially TH1 cells)
nonimmune cells (fibroblasts,
smooth muscle cells)

5. Pharmacokinetics
• TNF exists in two biologically active
forms: soluble TNF and membrane-
bound TNF.
• The biologic activity of soluble and
membrane-bound TNF is mediated
by binding to TNF receptors (TNFR).

6. Pharmacokinetics
TNFR are present on some cells, especially
TH1 cells, innate immune cells and
fibroblasts.
Binding of TNF to TNFR initially activates
components including NF-κB that stimulate
transcription, growth and expansion.

7. TNFR activation causes:
release of proinflammatory cytokines from
macrophages
T-cell activation and proliferation
fibroblast collagen production
up-regulation of endothelial adhesion molecules
responsible for leukocyte migration
stimulation of hepatic acute phase reactants

8. Pharmacokinetics
• Activation of TNFR may later lead to
apoptosis-programmed cell death of
activated cells.
• Monoclonal antibodies to human TNF
are approved for the treatment of
IBD: infliximab, adalimumab and
certolizumab.

9. Pharmacokinetics
• Infliximab and adalimumab are
antibodies of the IgG1 subclass.
• Certolizumab is a recombinant
antibody that contains an Fab
fragment that is conjugated to
polyethylene glycol (PEG), but lacks
an Fc portion.

10. Pharmacokinetics
• Infliximab is administered as
intravenous infusion.
• Therapeutic doses: 5-10 mg/kg.
• Half-life is 8-10 days.
• Plasma disappearance of
antibodies: over 8-12 weeks.

11. Pharmacokinetics
Adalimumab and certolizumab
are administered by
subcutaneous injection.
Half-life: 2 weeks.

12. Infliximab Adalimumab Certolizumab
Class Monoclonal antibody Monoclonal antibody Monoclonal antibody
% Human 75 100 95
Structure IgG1 IgG1 Fab fragment attached
to PEG (lacks Fc
portion)
Route of administration Intravenous Subcutaneous Subcutaneous
Half-life 8-10 days 10-20 days 14 days
Neutralizes soluble TNF Yes Yes Yes
Neutralizes membrane-
bound TNF
Yes Yes Yes
Induces apoptosis of
cells expressing
membrane-bound TNF
Yes Yes No
Complement-mediated
cytotoxicity of cells
expressing membrane-
bound TNF
Yes Yes No
Induction dose 5 mg/kg at 0, 2 and 6
weeks
160 mg, 80 mg and
20 mg at 0, 2 and 4
weeks
400 mg at 0, 2 and 4
weeks
Maintenance dose 5 mg/kg every 8 weeks 40 mg every 2 weeks 400 mg every 4 weeks

13. Pharmacodynamics
• All 3 agents bind to soluble and
membrane-bound TNF with high
affinity, preventing the cytokine from
binding to its receptors.
• Binding of these drugs to membrane-
bound TNF causes reverse signaling
that supresses cytokine release.

14. Pharmacodynamics
• When infliximab and adalimumab
bind to membrane-bound TNF, the
Fc portion of the human IgG1 region
promotes antibody-mediated
apoptosis, complement activation
and cellular cytotoxicity of activated T
lymphocytes and macrophages.

15. Clinical uses
• All three agents are approved for the
acute and chronic treatment of patients
with moderate to severe Crohn´s
disease (second line treatment).
• Infliximab is approved for the acute and
chronic treatment of moderate to severe
ulcerative colitis.

16. Clinical uses
• Median time to clinical response is
two weeks.
• One-third of patients lose response
despite higher doses or more
frequent injections, usually due to the
development of antibodies to the TNF
antibody.

17. Adverse effects
Serious adverse events occur in
up to 6% of patients with anti-TNF
therapy.
The most important is INFECTION
due to suppression of the TH1
inflammatory response.

18. Serious infections may occur:
• bacterial sepsis, TBC
• invasive fungal organisms
• reactivation of hepatitis B
• listeriosis
• reactivation of latent TBC with
dissemination

19. Warning!
Before administering anti-TNF
therapy, all patients must
undergo testing with tuberculin
skin tests or interferon gamma
release assays.

20. Adverse effects
The risk of serious
infections is increased
markedly in patients
taking concomitant
corticosteroids.

21. Adverse effects
More common and less
serious infections are
upper respiratory infections
(sinusitis, bronchitis,
pneumonia) and cellulitis.

22. Adverse effects
• Antibodies to the antibody (ATA) may
develop with all 3 agents.
• ATA may attenuate or eliminate the
clinical response.
• ATA may increase the likelihood of
developing acute or delayed infusion
or injection reactions.

23. Adverse effects
Antibody formation is much more
likely in patients given episodic
anti-TNF therapy than regular
scheduled injections.
Prevalence of ATA in patients on
chronic maintenance therapy:
infliximab 10%, certolizumab 8%
and adalimumab 3%.

24. Adverse effects
Antibody development is less likely in
patients who receive concomitant therapy
with immunomodulators (6-MP, MTX).
Concomitant treatment with anti-TNF
agents and immunomodulators may
increase the risk of lymphoma.

25. Adverse effects
Infliximab intravenous infusions
result in acute adverse infusion
reactions in up to 10% of patients.
Infusion reactions are more common
with the second or subsequent
infusions than with the first.

26. Adverse effects
• Early mild reactions are fever,
headache, dizziness, urticaria
and mild cardiopulmonary
symptoms (chest pain,
dyspnea, hemodynamic
instability).

27. Adverse effects
Prophylactic
administration of
acetaminophen,
diphenhydramine or
corticosteroids may
reduce reactions to
subsequent infusions.

28. Adverse effects
• Severe acute reactions are
significant hypotension,
shortness of breath, muscle
spasms and chest discomfort.
• Treatment: oxygen, epinephrine
and corticosteroids.

29. Adverse effects
Delayed serum sickness-like reactions
may occur 1-2 weeks after anti-TNF
therapy in 1% of the patients.
Myalgia, arthralgia, jaw tightness, fever,
rash, urticaria, edema: usually is
necessary discontinuation of that agent.

30. Adverse effects
• Positive antinuclear antibodies and
anti-double-stranded DNA develop
in a small number of patients.
• Development of a lupus-like
syndrome is rare and resolves after
discontinuation of the drug.

31. Rare and serious adverse effects are:
• severe hepatic reactions leading to
acute hepatic failure
• demyelinating disorders
• hematologic reactions
• new or worsened congestive heart
failure in patients with underlying
heart disease

32. Adverse effects
• Anti-TNF agents may cause a variety
of psoriatic skin rashes that usually
resolve after drug discontinuation.
• Lymphoma appears to be increased
in patients with untreated IBD.
• Anti-TNF agents may further increase
the risk of lymphoma.

33. Adverse effects
• An increased number of cases of
hepatosplenic T-cell lymphoma have
been noted in children and young
adults taking combined therapy with
immunomodulators, anti-TNF agents
or corticosteroids.

34. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.