Page 666 - Basic _ Clinical Pharmacology ( PDFDrive )

652 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

3. Dosage and Indications: It is recommended to start treatment inflammation by decreasing the presentation of antigens to T
with 7.5 mg weekly. According to patient response, methotrex- lymphocytes and inhibiting the secretion of proinflammatory
ate is increased to the most common dosing regimen for the cytokines. Rituximab rapidly depletes peripheral B cells,
treatment of RA, which is 15–25 mg weekly. Notably there is although this depletion correlates neither with efficacy nor with
an increased effect up to 30–35 mg weekly, although with toxicity.
increased toxicity. The drug decreases the rate of appearance of 2. Pharmacokinetics: Rituximab is given as two intravenous
new erosions. Evidence supports its use in juvenile chronic infusions of 1000 mg, separated by 2 weeks. It may be repeated
arthritis, and it has been used in psoriasis, PA, AS, polymyosi- every 6–9 months, as needed. Repeated courses remain effec-
tis, dermatomyositis, Wegener’s granulomatosis, giant cell tive. Pretreatment with acetaminophen, an antihistamine, and
arteritis, SLE, and vasculitis. intravenous glucocorticoids (usually 100 mg of methylpred-
4. Adverse Effects: Nausea and mucosal ulcers are the most com- nisolone) given 30 minutes prior to infusion decreases the
mon toxicities. Additionally, many other side effects such as incidence and severity of infusion reactions.
leukopenia, anemia, stomatitis, GI ulcerations, and alopecia 3. Indications: Rituximab is indicated for the treatment of mod-
are probably the result of inhibiting cellular proliferation. erately to severely active RA in combination with methotrexate
Progressive dose-related hepatotoxicity in the form of enzyme in patients with an inadequate response to one or more TNF-α
elevation occurs frequently, but cirrhosis is rare (<1%). Liver antagonists. Rituximab in combination with glucocorticoids is
toxicity is not related to serum methotrexate concentrations. A also approved for the treatment of adult patients with granulo-
rare hypersensitivity-like lung reaction with acute shortness of matosis with polyangiitis (previously known as Wegener’s
breath has been documented, as have pseudo-lymphomatous granulomatosis) and microscopic polyangiitis and is used in
reactions. The incidence of GI and liver function test abnor- other forms of vasculitis as well (see Chapter 54 for its use in
malities can be reduced by the use of leucovorin 24 hours after lymphomas and leukemias).
each weekly dose or by the use of folic acid, although this may 4. Adverse Effects: About 30% of patients develop rash with the
decrease the efficacy of the methotrexate by about 10%. This first 1000-mg treatment; this incidence decreases to about 10%
drug is contraindicated in pregnancy. with the second infusion and progressively decreases with each
course of therapy thereafter. These rashes do not usually require
discontinuation of therapy, although an urticarial or anaphy-
MYCOPHENOLATE MOFETIL lactoid reaction precludes further therapy. Immunoglobulins
(particularly IgG and IgM) may decrease with repeated courses
1. Mechanism of Action: Mycophenolate mofetil (MMF), a csD- of therapy and infections can occur, although they do not seem
MARD, is converted to mycophenolic acid, the active form of directly associated with the decreases in immunoglobulins.
the drug. The active product inhibits inosine monophosphate Serious, and sometimes fatal, bacterial, fungal, and viral infec-
dehydrogenase, leading to suppression of T- and B-lymphocyte tions are reported for up to 1 year of the last dose of ritux-
proliferation. Downstream, it interferes with leukocyte adhesion imab, and patients with severe and active infections should not
to endothelial cells through inhibition of E-selectin, P-selectin, receive rituximab. Rituximab is associated with reactivation of
and intercellular adhesion molecule 1. MMF’s pharmacokinetics hepatitis B virus (HBV) infection, which requires monitoring
and toxicities are discussed in Chapter 55. before and several months after the initiation of the treatment.
2. Indications: MMF is effective for the treatment of renal dis- Rituximab has not been associated with either activation of
ease due to SLE and may be useful in vasculitis and Wegener’s tuberculosis or the occurrence of lymphomas or other tumors
granulomatosis. Although MMF is occasionally used at a dos- (see Chapter 55). Fatal mucocutaneous reactions have been
age of 2 g/d to treat RA, there are no well-controlled data reported in patients receiving rituximab. Different cytopenias
regarding its efficacy in this disease. can occur, which require complete blood cell monitoring every
3. Adverse Effects: MMF is associated with nausea, dyspepsia, 2–4 months in RA patients. Other adverse effects, such as
and abdominal pain. Like azathioprine, it can cause hepato- cardiovascular events, are rare.
toxicity. MMF can also cause leukopenia, thrombocytopenia,
and anemia. MMF is associated with an increased incidence of
infections. It is only rarely associated with malignancy. SULFASALAZINE

1. Mechanism of Action: Sulfasalazine, a csDMARD, is metabo-
RITUXIMAB lized to sulfapyridine and 5-aminosalicylic acid. The sulfapyri-
dine is probably the active moiety when treating RA (unlike
1. Mechanism of Action: Rituximab is a chimeric monoclonal inflammatory bowel disease; see Chapter 62). Some authorities
antibody biologic agent that targets CD20 B lymphocytes (see believe that the parent compound, sulfasalazine, also has an
Chapter 55). Depletion of these cells takes place through cell- effect. Suppression of T-cell responses to concanavalin and
mediated and complement-dependent cytotoxicity and stimu- inhibition of in vitro B-cell proliferation are documented. In
lation of cell apoptosis. Depletion of B lymphocytes reduces vitro, sulfasalazine or its metabolites inhibit the release of