A Textbook of Clinical Pharmacology and Therapeutics

Table 50.1: Novel anti-proliferative immunosuppressants
cardiac) transplantation and is a more effective alternative than
azathioprine. Mycophenolate mofetil may also be effective in
the treatment of other autoimmune disorders, such as rheumatoid
arthritis and psoriasis.
Mechanism of action
In vivo the active entity, mycophenolic acid, inhibits inosine
monophosphate dehydrogenase (a pivotal enzyme in purine
synthesis). It suppresses proliferation both of T and B
lymphocytes. In addition, mycophenolic acid inhibits the
production of pro-inflammatory cytokines.
Adverse effects
These include the following:
• gastro-intestinal disturbances – diarrhoea and
haemorrhage;
• bone marrow suppression, especially leukopenia and
anaemia;
• CMV infection;
• lymphomas.
Pharmacokinetics
Mycophenolate mofetil is a prodrug ester of mycophenolic
acid, with improved absorption. After oral administration in
humans, the ester is rapidly and completely cleaved to
mycophenolic acid. Mycophenolic acid undergoes hepatic
elimination to its inactive glucuronide metabolite.
Drug interactions
Antacids decrease mycophenolate absorption.
For novel anti-proliferative agents, such as sirolimus and
everolimus – see Table 50.1.
BIOLOGIC IMMUNOSUPPRESSANTS
POLYCLONAL ANTIBODIES
ANTILYMPHOCYTE GLOBULIN
Antilymphocyte globulin (ALG, also known as antithymocyte
globulin) is prepared by injecting human T lymphocytes
into animals (e.g. rabbits or horses) to raise antibodies. The
active immunoglobulin is largely in the IgG fraction and ALG
is a polyclonal antilymphocyte antibody with inherent variability
from batch to batch. The major effect is probably to prevent
antigen from accessing the antigen-recognition site on
the T-helper cells. It is given intravenously for acute organ
transplant rejection. Adverse effects include anaphylaxis and
serum sickness.
MONOCLONAL ANTIBODIES
ANTI-CD3 ANTIBODY (MUROMONAB-CD3)
Uses
These monoclonal antibodies are used as adjuvant (often as
second-line) immunosuppressive therapy in patients with
acute transplant rejection. They are IgG2a antibodies produced
from murine hybridoma cells and are given intravenously.
After a 10- to 14-day course, some patients develop neutralizing
antibodies.
Mechanism of action
Anti-CD3 antibodies bind CD3 protein, blocking antigen
binding to the T-cell antigen–recognition complex, and
decreasing the number of circulating CD3-positive lymphocytes.
In addition, binding of anti-CD3 to its receptor causes
cytokine release (see Adverse effects below). The overall effect
is to reduce T-cell activation in acute solid-organ graft
rejection.
Adverse effects
These include the following:
IMMUNOSUPPRESSIVE AGENTS 403
Drug Comments on use Side effects Pharmacokinetics
Sirolimus (rapamycin) Used with ciclosporin to Mild gastro-intestinal Well absorbed. Elimination t1/2 is
prevent graft rejection disturbances. Thrombocytopenia 57 h. Hepatic metabolism by CYP3A.
leukopenia, anaemia, increased
cholesterol and triglycerides.
Not nephrotoxic
Linear kinetics
Molecular target/mechanism: Drug interactions similar to Therapeutic drug monitoring advised
binds and inhibits mTOR, a ciclosporin. Sirolimus AUC
protein kinase involved in increased if given with
cell cycle progression ciclosporin
Everolimus Analogue of sirolimus Shorter t 1/2 than sirolimus
mTOR, mammalian target of rapamycin.
• cytokine release syndrome, with chest pain, wheezing and
dyspnoea (pulmonary oedema occurs after the first dose
in 1% of patients);
• hypersensitivity reactions ranging from anaphylaxis to an
acute influenza-like syndrome;
• CNS effects – seizures, reversible meningo-encephalitis
and cerebral oedema.