Patricia A. Walicke

Safety of efalizumab in adults with chronic moderate to severe plaque psoriasis: a phase IIIb, randomized, controlled trial.

Background  To provide safety data for efalizumab, a recombinant humanized monoclonal IgG1 antibody, in adults with chronic plaque psoriasis.

An Overview of the Pharmacokinetics and Pharmacodynamics of Efalizumab: A Monoclonal Antibody Approved for Use in Psoriasis

Efalizumab is a recombinant humanized monoclonal IgG1 antibody shown to be efficacious for the treatment of moderate to severe chronic plaque psoriasis. Efalizumab, a targeted inhibitor of T cell interactions, binds to the CD11a subunit of lymphocyte function—associated antigen 1 (LFA‐1), thereby preventing LFA‐1 binding to intercellular adhesion molecule 1 (ICAM‐1). The authors review the pharmacokinetic and pharmacodynamic data from the efalizumab clinical development program and discuss how these data led to selection of the optimal weekly subcutaneous (SC) dose of efalizumab (1.0 mg/kg) in adults. Efalizumab SC dosages of 1.0 mg/kg/wk or greater exerted maximal pharmacodynamic effects for CD11a expression and available CD11a binding sites on T lymphocytes. Dosages greater than 1.0 mg/kg/wk SC did not provide additional benefits; moreover, higher doses did not alter the safety profile. During long‐term administration of efalizumab, serum levels were generally stable and pharmacodynamic markers remained maximally affected.

Anti-adhesion antibodies efalizumab, a humanized anti-CD11a monoclonal antibody.

The acquired immune response that leads to graft rejection depends on regulated adhesive interactions between T lymphocytes, endothelial cells, dendritic cells, graft tissue and the extracellular matrix to coordinate cellular trafficking and activation of antigen-reactive T lymphocytes. Inhibiting the function of molecules involved in the adhesion processes offers the potential for interfering with the allograft response. The leukocyte function associated antigen-1 molecule (LFA-1), a heterodimer of CD11a (alphaL) and CD18 (beta2) integrin subunits, is an attractive therapeutic target because it plays an important role in key steps of inflammation and tissue rejection. These include: (1) binding of leukocytes to endothelium; (2) trafficking through activated endothelium; and (3) costimulatory interactions between T lymphocytes and antigen presenting cells. Clinical experience with efalizumab, a humanized anti-CD11a monoclonal antibody (mAb), in patients with chronic plaque psoriasis has shown that anti-CD11a therapy is well tolerated and effective at reducing the severity of the disease without depleting lymphocytes. Initial results in renal transplant patients are also promising.

Pharmacokinetics and pharmacodynamics of multiple weekly subcutaneous efalizumab doses in patients with plaque psoriasis.

Efalizumab pharmacokinetics, pharmacodynamics, and efficacy were assessed after subcutaneous administration of 1.0 or 2.0 mg/kg/wk for 12 weeks with 12 weeks of follow‐up in subjects with psoriasis. Steady‐state serum concentrations were achieved by 4 and 8 weeks, respectively. Cmax was 12 and 31 μg/mL, occurring ∼2 days after a SC dose. Serum trough levels were 9 and 24 μg/mL, and CL/Fss was 24 and 16 mL/kg/d. At both doses, CD11a expression on T lymphocytes was maximally down‐modulated to ∼20% of baseline, and CD11a binding sites were >95% saturated. The extent of this PD effect was less for other leukocytes. Leukocyte counts increased by ∼40%, with the majority of this increase related to a significant but reversible increase in the lymphocyte population. Maximal pharmacodynamic effects were sustained at both dose levels through the course of treatment and were commensurate with improvements in psoriasis.

Chronic treatment with efalizumab does not deplete lymphocytes as seen in PK/PD study ACD2142G

Clinical Pharmacology & Therapeutics (2003) 73, P53–P53; doi: