Page 1124 - Basic _ Clinical Pharmacology ( PDFDrive )

1110 SECTION X Special Topics

bone marrow depression. TPMT levels can be measured before used in the treatment of IBD, these events are uncommon but
initiating therapy. These drugs should not be administered to warrant dose reduction if they do occur. Folate supplementa-
patients with no TPMT activity and should be initiated at lower tion reduces the risk of these events without impairing the anti-
doses in patients with intermediate activity. Hypersensitivity reac- inflammatory action.
tions to azathioprine or 6-MP occur in 5% of patients. These In patients with psoriasis treated with methotrexate, hepatic
include fever, rash, pancreatitis, diarrhea, and hepatitis. damage is common; however, among patients with IBD and rheu-
As with transplant recipients receiving long-term 6-MP or matoid arthritis, the risk is significantly lower. Renal insufficiency
azathioprine therapy, there appears to be an increased risk of lym- may increase risk of hepatic accumulation and toxicity.
phoma among patients with IBD, some of which may be related
to Epstein-Barr virus infection. The drugs are also associated with ANTITUMOR NECROSIS FACTOR
an increased risk of nonmelanoma skin cancers. These drugs cross THERAPY
the placenta; however, there are many reports of successful preg-
nancies in women taking these agents, and the risk of teratogenic- Pharmacokinetics & Pharmacodynamics
ity appears to be small.
A dysregulation of the helper T cell type 1 (Th1) response and regu-
Drug Interactions latory T cells (Tregs) is present in IBD, especially Crohn’s disease.
One of the key proinflammatory cytokines in IBD is tumor necrosis
Allopurinol markedly reduces xanthine oxide catabolism of the factor (TNF). TNF is produced by the innate immune system (eg,
purine analogs, potentially increasing active 6-thioguanine nucle- dendritic cells, macrophages), the adaptive immune system (espe-
otides that may lead to severe leukopenia. Allopurinol should not cially Th1 cells), and nonimmune cells (fibroblasts, smooth muscle
be given to patients taking 6-MP or azathioprine except in care- cells). TNF exists in two biologically active forms: soluble TNF
fully monitored situations.
and membrane-bound TNF. The biologic activity of soluble and
membrane-bound TNF is mediated by binding to TNF receptors
METHOTREXATE (TNFR) that are present on some cells (especially Th1 cells, innate
immune cells, and fibroblasts). Binding of TNF to TNFR initially
Pharmacokinetics & Pharmacodynamics activates components including NF-κB that stimulate transcrip-
tion, growth, and expansion. Biologic actions ascribed to TNFR
Methotrexate is another antimetabolite that has beneficial effects activation include release of proinflammatory cytokines from
in a number of chronic inflammatory diseases, including Crohn’s macrophages, T-cell activation and proliferation, fibroblast col-
disease and rheumatoid arthritis (see Chapter 36), and in cancer lagen production, up-regulation of endothelial adhesion molecules
(see Chapter 54). Methotrexate may be given orally, subcutane- responsible for leukocyte migration, and stimulation of hepatic
ously, or intramuscularly. Reported oral bioavailability is 50–90% acute phase reactants. Activation of TNFR may later lead to apop-
at doses used in chronic inflammatory diseases. Intramuscular and tosis (programmed cell death) of activated cells.
subcutaneous methotrexate exhibit nearly complete bioavailability. Four monoclonal antibodies to human TNF are approved
The principal mechanism of action is inhibition of dihydrofolate for the treatment of IBD: infliximab, adalimumab, golimumab,
reductase, an enzyme important in the production of thymidine and certolizumab (Table 62–3). Infliximab, adalimumab, and
and purines. At the high doses used for chemotherapy, methotrexate golimumab are antibodies of the IgG subclass. Certolizumab
1
inhibits cellular proliferation. However, at the low doses used in the is a recombinant antibody that contains an Fab fragment that is
treatment of IBD (12–25 mg/wk), the antiproliferative effects may conjugated to polyethylene glycol (PEG) but lacks an Fc portion.
not be evident. Methotrexate may interfere with the inflammatory The Fab portion of infliximab is a chimeric mouse-human anti-
actions of IL-1. It may also stimulate increased release of adenosine, body, but adalimumab, certolizumab, and golimumab are fully
an endogenous anti-inflammatory autacoid. Methotrexate may also humanized. Infliximab is administered as an intravenous infusion.
stimulate apoptosis and death of activated T lymphocytes. At therapeutic doses of 5–10 mg/kg, the half-life of infliximab
is approximately 8–10 days, resulting in plasma disappearance
Clinical Uses of antibodies over 8–12 weeks. Adalimumab, golimumab, and
certolizumab are administered by subcutaneous injection. Their
Methotrexate is used to induce and maintain remission in patients
with Crohn’s disease. Its efficacy in ulcerative colitis is uncertain. half-lives are approximately 2 weeks.
To induce remission, patients are treated with 15–25 mg of All four agents bind to soluble and membrane-bound TNF
methotrexate once weekly by subcutaneous injection. If a satisfac- with high affinity, preventing the cytokine from binding to its
tory response is achieved within 8–12 weeks, the dose is reduced receptors. Binding of all three antibodies to membrane-bound
to 15 mg/wk. TNF also causes reverse signaling that suppresses cytokine release.
When infliximab, adalimumab, or golimumab bind to membrane-
Adverse Effects bound TNF, the Fc portion of the human IgG region promotes
1
antibody-mediated apoptosis, complement activation, and cellular
At higher dosage, methotrexate may cause bone marrow depres- cytotoxicity of activated T lymphocytes and macrophages. Certoli-
sion, megaloblastic anemia, alopecia, and mucositis. At the doses zumab, without an Fc portion, lacks these properties.