Efalizumab is a recombinant humanized monoclonal antibody that binds specifically to the CD11a subunit of LFA-1 (lymphocyte function-associated antigen-1), a leukocyte cell surface protein.
By this mechanism, efalizumab inhibits the binding of LFA-1 to ICAM-1, which interferes with T lymphocytes adhesion to other cell types. LFA-1 is present on activated T lymphocytes, and ICAM-1 is up-regulated on endothelial cells and keratinocytes in psoriasis plaques. By preventing LFA-1/ICAM binding, efalizumab may alleviate signs and symptoms of psoriasis by inhibiting several stages in the immunologic cascade.
In studies using an initial dose of 0.7 mg/kg followed by 11 weekly doses of 1.0 mg/kg, efalizumab maximally reduced expression of CD11a on circulating T lymphocytes to approximately 15-30% of pre-dose baseline values and saturated CD11a to <5% of baseline available CD11a binding sites. The full effect was seen 24 to 48 hours after the first dose, and was maintained between weekly doses. Within 5 to 8 weeks following the 12th and final dose of efalizumab administered at 1.0 mg/kg/wk, CD11a levels returned to within a range of ±25% of baseline values.
Another pharmacodynamic marker, consistent with the mechanism of action of efalizumab, was the increase in the absolute counts of circulating leukocytes observed during efalizumab treatment. Increased absolute counts were apparent within 24 hours of the first dose, remained elevated with weekly dosing, and returned to baseline after treatment cessation. The largest increase occurred in the absolute count of circulating lymphocytes. In clinical trials, mean lymphocyte counts approximately doubled relative to baseline in subjects receiving 1.0 mg/kg/wk of efalizumab. The increase included CD4 T-lymphocytes, CD8 T-lymphocytes, B-lymphocytes, and natural killer (NK) cells, although NK cells and CD4 cells increased less relative to other cell types. At a dose of 1.0 mg/kg/wk subcutaneous efalizumab, lymphocyte levels returned to within 10% of baseline by 8 weeks post last dose.
After subcutaneous administration of efalizumab peak plasma concentrations are reached after 1-2 days. Comparison with intravenous data indicated an average bioavailability of about 50% at the recommended dose level of 1.0 mg/kg/wk subcutaneous.
Steady state was achieved at week 4. At the 1 mg/kg/wk dose level (with an initial dose of 0.7 mg/kg the first week), mean efalizumab plasma trough values were 11.1±7.9 µg/ml. Measurements of volume of distribution of the central compartment after single intravenous doses were 110 ml/kg at dose 0.03 mg/kg and 58 ml/kg at dose 10 mg/kg.
The metabolism of efalizumab is through internalisation followed by intracellular degradation as a consequence of either binding to cell surface CD11a or through endocytosis. The expected degradation products are small peptides and individual amino acids which are eliminated by glomerular filtration. Cytochrome P450 enzymes as well as conjugation reactions are not involved in the metabolism of efalizumab.
Efalizumab is cleared by nonlinear saturable elimination (dose dependent). Mean steady state clearance is 24 ml/kg/day (range 5-76 ml/kg/day) at 1 mg/kg/week subcutaneous. The elimination half-life was about 5.5-10.5 days at 1 mg/kg/week subcutaneous. Tend at steady state is 25 days (range 13-35 days). Weight is the most significant covariate affecting efalizumab clearance.
Efalizumab shows dose-dependent nonlinear pharmacokinetics which can be explained by its saturable specific binding to cell surface receptors CD11a. It appeared that the receptor mediated clearance of efalizumab was saturated when plasma efalizumab concentrations were above 1 μg/ml.
Through population pharmacokinetic analysis, weight was found to affect efalizumab clearance. Covariates as baseline PASI, baseline lymphocyte count and age had modest effects on clearance; gender and ethnic origin had no effect. The pharmacokinetics of efalizumab in paediatric patients have not been studied. The effect of renal or hepatic impairment on the pharmacokinetics of efalizumab has not been studied.
Antibodies to efalizumab were detected in only 6% of patients evaluated. In this small number of patients no differences were observed in either pharmacodynamic or pharmacokinetic parameters.
Efalizumab does not cross-react with CD11a from species other than humans and chimpanzees. Therefore, conventional non-clinical safety data with the medicinal product are limited and do not allow for a comprehensive safety assessment. Inhibitory effects were observed on the humoral and T-cell dependent immune responses. In pups of mice treated with an antibody analogue of efalizumab, a decrease in T-cell dependent immunity was observed up to at least 11 weeks of age. Only at 25 weeks of age was this decrease no longer significant.
Otherwise, the effects observed in non-clinical studies could be related to the pharmacology of efalizumab.
No lymphomas were observed following 6 months treatment with an antibody analogue of efalizumab in a 6 months study with p53 / wild type mice.
No teratogenic effects were seen in mice during organogenesis.
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