Adalimumab dosing

Adalimumab (Humira) is a human immunoglobulin Gj monoclonal TNF-a antibody. The binding of adalimumab results in inactivation of the proinflammatory cytokine TNF-a. It is indicated for psoriatic arthritis and treatment of adults with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. The recommended dose for psoriatic arthritis is 40 mg subcutaneously every other week. The recommended dose for adults with plaque psoriasis is an initial dose of 80 mg, followed by 40 mg every other week starting 1 week after the initial dose. The most common adverse reactions are infections (e.g., upper respiratory, sinusitis), injection site reactions, headache, and rash. 

Infliximab is used for moderate to severe active Crohn s disease in patients failing immunosuppressive therapy, in those who are corticosteroid dependent, and for treatment of fistulizing disease. A single, 5 mg/kg infusion is effective when given every day for 8 weeks. Additional doses at 2 and 6 weeks following the initial dose results in higher response rates. Adalimumab is effective in 54% of patients with moderate to severe Crohn s disease who have lost response to infliximab. The typical dosage is 160 mg subcutaneously initially, followed by 80 mg subcutaneously at week 2, with subsequent doses of 40 mg subcutaneously every other week thereafter. 

Adalimumab is given subcutaneously and has a half-life of 10-20 days. Its clearance is decreased by more than 40% in the presence of methotrexate, and the formation of human antimonoclonal antibody is decreased when methotrexate is given at the same time. The usual dose in rheumatoid arthritis is 40 mg every other week, although increased responses may be evident at higher dosages. In psoriasis, 80 mg is given at week 0, 40 mg at week 1, and then 40 mg every other week thereafter. 

Adalimumab is a completely human IgGi approved for use in rheumatoid arthritis. Like the other anti-TNF- biologicals, adalimumab blocks the interaction of TNF- with TNF receptors on cell surfaces it does not bind TNF-3. Pharmacodynamic studies showed that administration of adalimumab reduced levels of C-reactive protein, erythrocyte sedimentation rate, serum IL-6, and matrix metalloproteinases MMP-1 and MMP-3. In vitro, adalimumab lyses cells expressing TNF- in the presence of complement. Patients may self-administer single doses of the antibody subcutaneously, every other week. Adalimumab has a serum half-life of 2 weeks, which is increased by 29-44% in patients who are also taking methotrexate. 

Adalimumab (Humira) is a recombinant lgGi monoclonal antibody that binds specifically to TNF-o. and blocks its interaction with cell surface TNF receptors. The recommended dose for adalimumab in psoriasis is an initial dose of 80 mg administered subcutaneously followed by 40 mg given every other week starting 1 week after the initial dose. 

Three monoclonal antibodies to human TNF are approved for the treatment of inflammatory bowel disease infliximab, adalimumab, and certolizumab (Table 62-3). Infliximab and adalimumab are antibodies of the IgGi subclass. Certolizumab is a recombinant antibody that contains an Fab fragment that is conjugated to polyethylene glycol (PEG) but lacks an Fc portion. The Fab portions of infliximab and certolizumab are chimeric mouse-human antibodies but adalimumab is fully humanized. Infliximab is administered as an intravenous infusion. At therapeutic doses of 5-10 mg/kg, the half-life of infliximab is approximately 8-10 days, resulting in plasma disappearance of antibodies over 8-12 weeks. Adalimumab and certolizumab are administered by subcutaneous injection. The half-life for both is approximately 2 weeks. 

Adalimumab is used to reduce signs and symptoms and progression of rheumatoid arthritis and psoriatic arthritis. It could be administered alone or in combination with methotrexate. The recommended dose for adults is 40 mg by subcutaneous injection, administered every other week. The most common side effect associated with the administration of adalimumab is injection site reaction. The most serious side effects resulting from treatment with this antibody include increased risk of infections and malignancies and neurological disorders. Additional side effects are the production of autoantibodies, immunogenicity and GI disorders. 

The compound is indicated for the treatment of rheumatoid arthritis and decreases the rate of formation of new erosions. It is effective both as monotherapy and in combination with methotrexate. The usual dose is 40 mg every other week, though increased responses may be evident at higher dosages. Adalimumab is presently being tested in psoriasis, psoriatic arthritis, ankylosing spondylitis, and juvenile chronic arthritis. 

Due to their high molecular mass (and other reasons), the vast majority of mAbs that have been approved or are currently in clinical development are administered by intravenous (IV) infusion. This route allows the total dose to be available in the circulation, as F (the systemically available fraction of the dose) is, by definition, 1. In consequence, maximum concentrations in serum are rapidly observed, and are higher compared to those achieved by other routes. Therefore, adverse reactions after IV administration occur more often but are generally reversible. In addition, IV infusions represent the most inconvenient (they often require hospitalization) as well as time- and cost-consuming means of administration. Consequently, ex-travascular routes have been chosen as alternatives, including subcutaneous administration (SC e. g., adalimumab, efalizumab) and intramuscular administration (IM e.g., palivizumab) (Table 3.4). 

Fig. 12.8 (A) Dose-response relationship for adalimumab following singledose administration in patients with rheumatoid arthritis. (Figure produced from data reported in [78]). (B) Simulated suppression of serum TNF-a following single-dose administration of adalimumab.

O. Sander, C. Binder, H. Fenner,Y. Bank-mann, R. Velagapudi, J. Kempeni, and H. Kupper. 2002. A single dose, placebo controlled study of the fully human antitumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis./. Rheumatol. 29 2288-2298. 

Adalimumab is supplied in single-use, prefilled, glass syringes as a sterile, preservative-free, colorless solution for subcutaneous administration. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single IV dose. The mean elimination half-life was approximately 2 weeks. 

Cardiovascular A severe cardiomyopathy after treatment with adalimumab for Crohn s disease has been reported in a 25-year-old patient 1 week after the initial dose [23 ]. 

Immunologic An IgE-mediated anaphylactic reaction has been attributed to anakinra in a 46-year-old Indian woman with rheumatoid arthritis who had had an urticarial rash and infusion reactions after three doses of infliximab, and autoantibodies, worsening Raynaud s phenomenon, and digital microinfarcts after treatment with etanercept for 1 year [83 ]. Skin prick tests were positive to both anakinra and histamine. She then had an urticarial reaction to adalimumab. 

Cardiovascular A severe cardiomyopathy occurred 1 week after a single dose of adalimumab in a 25-year-old woman with Crohn s disease [94 ]. 

All three drugs appear to have linear pharmacokinetics (296). A loading dose of two treatments two weeks apart seems important. In addition, a similar loading dose schedule was beneficial in using adalimumab for Crohn s disease (278). Autoantibodies can develop against these agents, especially infliximab (280,297). 

Liver Approximately 1 in 10 cases of autoimmune hepatitis is triggered by drugs [80 ]. After 2 months and six doses of adalimumab, a 52-year-old woman developed malaise and liver damage diagnosed as autoimmune hepatitis on fhe basis of elevations of hepatobiliary enzymes, positive conversion of antinuclear antibodies, high IgG levels and liver biopsy which showed portal lymphoplasmacytic inflammation, periportal interface hepatitis and lobular necroinflammatory changes [80 ]. 

A 53-year-old woman with rheumatoid arthritis developed a severe mucositis, peripheral rash, desquamation and fever after 5 doses of adalimumab. Infection was excluded and the patient responded rapidly to intravenous hydrocortisone. Stevens-Johnson syndrome was diagnosed and therapy was switched to infliximab without recurrence of the toxidermia [82 ]. 

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