RAPTIVA binds to CD11a, the α subunit of leukocyte function antigen-1 (LFA-1), which is expressed on all leukocytes, and decreases cell surface expression of CD11a. RAPTIVA inhibits the binding of LFA-1 to intercellular adhesion molecule-1 (ICAM-1), thereby inhibiting the adhesion of leukocytes to other cell types. Interaction between LFA-1 and ICAM-1 contributes to the initiation and maintenance of multiple processes, including activation of T lymphocytes, adhesion of

T lymphocytes to endothelial cells, and migration of T lymphocytes to sites of inflammation including psoriatic skin. Lymphocyte activation and trafficking to skin play a role in the pathophysiology of chronic plaque psoriasis. In psoriatic skin, ICAM-1 cell surface expression is upregulated on endothelium and keratinocytes. CD11a is also expressed on the surface of B lymphocytes, monocytes, neutrophils, natural killer cells, and other leukocytes. Therefore, the potential exists for RAPTIVA to affect the activation, adhesion, migration, and numbers of cells other than T lymphocytes.

Pharmacokinetics

In patients with moderate to severe plaque psoriasis, following an initial SC RAPTIVA dose of 0.7 mg/kg followed by 11 weekly SC doses of 1 mg/kg/wk, serum concentrations reached a steady-state at 4 weeks with a mean trough concentration of approximately 9 µg/mL (n = 26). After the last dose, the mean peak concentration was approximately 12 µg/mL (n=25). Mean steady-state clearance was 24 mL/kg/day (range = 5-76 mL/kg/day, n = 25). Mean time to eliminate RAPTIVA after the last steady-state dose was 25 days (range= 13-35 days, n= 17). The mean estimated RAPTIVA SC bioavailability was 50%. In a population pharmacokinetic analysis of 1088 patients, body weight was found to be the most significant covariate affecting RAPTIVA clearance. In patients receiving weekly SC doses of 1 mg/kg, RAPTIVA exposure was similar across body weight quartiles. RAPTIVA clearance was not significantly affected by gender or race. The pharmacokinetics of RAPTIVA in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of RAPTIVA have not been studied.

Pharmacodynamics

At a dose of 1 mg/kg/wk SC, RAPTIVA reduced expression of CD11a on circulating T lymphocytes to approximately 15-25% of pre-dose values and reduced free CD11a binding sites to a mean of †¤5% of pre-dose values. These pharmacodynamic effects were seen 1-2 days after the first dose, and were maintained between weekly 1 mg/kg SC doses. Following discontinuation of RAPTIVA, CD11a expression returned to a mean of 74% of baseline at 5 weeks and stayed at comparable levels at 8 and 13 weeks. Following discontinuation of RAPTIVA, free CD11a binding sites returned to a mean of 86% of baseline at 8 weeks and stayed at comparable levels at 13 weeks. No assessments of CD11a expression or free CD11a binding sites were made after 13 weeks.

In clinical trials, RAPTIVA treatment resulted in a mean increase (relative to baseline) in white blood cell (WBC) count of 34%, a doubling of mean lymphocyte counts and an increase in eosinophil counts of 29% due to decreased leukocyte adhesion to blood vessel walls and decreased trafficking from the vascular compartment to tissues. At Day 56 of 1  mg/kg/wk RAPTIVA treatment, 32% (213/676) of patients had a shift in total WBC from low or normal baseline value to above normal, 46% (324/701) had a shift to above normal absolute lymphocyte counts, and 5% (35/675) had a shift to above normal eosinophil counts. Following discontinuation of RAPTIVA treatment, the abnormal elevated lymphocyte counts took approximately 8 weeks to normalize among patients who had above normal lymphocyte counts. Plasma samples collected after first administration of 0.3 mg/kg IV RAPTIVA indicate that at 2 hours TNF-α and IL-6 plasma levels were elevated 9- and 90-fold, respectively, compared with baseline. Plasma samples collected after first administration of 0.7 mg/kg SC RAPTIVA indicate that at 2 days, IL-6 levels were elevated (10 pg/mL as compared with 5 pg/mL at baseline), whereas TNF-α was not detectable. In RAPTIVA-treated patients the mean levels of C reactive protein increased from baseline by 67% and the mean levels of fibrinogen increased by 15%.

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