Peter Compton

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.

A review of malignancies observed during efalizumab (Raptiva®) clinical trials for plaque psoriasis

Background: Psoriasis is a chronic, incurable immune-mediated disease. Most therapies used for moderate to severe psoriasis are immunosuppressive. Agents that depress immune function, including traditional psoriasis therapies, have been associated with an increased incidence of malignancies. Efalizumab is a recombinant monoclonal immunoglobulin G1 (IgG1) antibody approved for use in psoriasis patients. Objectives: To evaluate the incidence of malignancy in patients receiving efalizumab during clinical trials compared with placebo-treated patients, psoriasis patients from external cohorts and the general US population. Methods: Patient data were pooled from multiple phase III placebo-controlled, open-label efalizumab clinical trials, and the incidence rate of reported malignancies was calculated as a function of patient years of observation. The results for the efalizumab-treated patients were compared with the data on psoriasis patients from insurance claims databases and a registry of events in the general population. Results: The efalizumab- and placebo-treated patients had similar incidence rates of malignancy, including lymphoproliferative disease, solid tumor, malignant melanoma and nonmelanoma skin cancer. The incidence of nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma, in patients receiving efalizumab or placebo was elevated relative to the external databases. Conclusions: These results suggest that efalizumab treatment does not increase a patient’s risk for malignancy. The difference observed with nonmelanoma skin cancer may be due to biases introduced by the clinical trial methodology. Additional patient observation is necessary to ascertain whether a link exists between efalizumab therapy and nonmelanoma skin cancer above that normally observed in psoriasis patients.

Population Pharmacokinetics of Efalizumab (Humanized Monoclonal Anti‐CD11a Antibody) Following Long‐Term Subcutaneous Weekly Dosing in Psoriasis Subjects

The population pharmacokinetics of efalizumab was characterized in patients with moderate to severe plaque psoriasis. The study included 1088 subjects who received 1 or 2 mg/kg/wk subcutaneous efalizumab for 12 weeks from a phase I (64 subjects) and 3 phase III studies with day 42 and/or day 84 trough levels (1024 patients). Due to the limitation of the data, a 1‐compartment model with first‐order absorption and elimination was used to fit the data. The population means for V/F, Ka, and CL/F were 9.13 L, 0.191 day−1, and 1.29 L/d, respectively, for a typical subject receiving a 1‐mg/kg dose. Interindividual variability in CL/F was 48.2%. Body weight has the largest influence on CL/F. Other covariates (obesity, baseline lymphocyte counts, Psoriasis Area and Severity Index score, and age) had only modest effects. Subjects in the 2‐mg/kg dose group had a 24.0% lower CL/F, consistent with nonlinear pharmacokinetics of efalizumab. The results of this analysis support the current body weight‐adjusted dosing strategy.

Safety of Efalizumab Therapy in Patients with Moderate to Severe Psoriasis An Open-Label Extension of a Phase IIIb Trial

AbstractBackground: Psoriasis is a chronic autoimmune disease characterized by infiltration of the dermis and epidermis by activated T cells and the hyperproliferation and abnormal differentiation of keratinocytes. It is a life-long disease with alternating periods of remission and recurrence. Efalizumab is a humanized, recombinant, T-cell targeting monoclonal antibody, approved for use in adults with chronic moderate to severe plaque psoriasis. Objective: To assess the safety of continued or newly initiated treatment with efalizumab for up to 48 weeks in patients with psoriasis who were treated previously with efalizumab or placebo. Methods: This study was an open-label, 48-week extension of a previously published 12-week, randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase IIIb study, carried out in the US and Canada between 24 October 2002 and 2 July 2004. Patients were followed and treated at the study clinic in an outpatient setting and also were trained to self-administer the drug at home. Patients comprising individuals with chronic moderate to severe plaque psoriasis who had completed the 12-week, placebo-controlled segment of the study were eligible for enrolment in the extension phase. Of the 686 patients enrolled in the study, 636 (92.7%) enrolled in the open-label extension of the study, 418 of whom had received 12 weeks of efalizumab therapy and 218 of whom had received 12 weeks of placebo. All patients entering the open-label phase of the study received efalizumab 1 mg/kg/wk for an additional 48 weeks, for a maximum exposure of up to 60 weeks. Safety was evaluated by an assessment of adverse events, including infections and serious adverse events. Results: The rate of withdrawal due to adverse events remained low throughout the trial, ranging from 1.2% to 6.6% during the 12-week segments of the open-label extension phase of the trial. The incidence of adverse events decreased with increased exposure to efalizumab; the incidence during the initial 12 weeks of exposure to efalizumab was 79.0% compared with 72.9% for patients exposed to placebo. Patients treated with efalizumab for 13–24 weeks, 25–36 weeks, 37–8 weeks and 49–60 weeks experienced adverse events at an incidence of 66.8%, 54.3%, 49.6% and 48.5%, respectively. The incidence of serious adverse events ranged from 1.6% to 3.5% during the 12-week segments of efalizumab therapy, compared with an incidence of 3.4% for placebo-treated patients. The incidence of infection ranged from 9.9% to 14.7% during the 12-week segments of efalizumab therapy, compared with an incidence of 19.1% for placebo-treated patients. Malignancies were reported with an incidence of ≤1.0% for efalizumab-treated patients during any 12-week segment compared with 0.4% for the 12-week placebo-treated patients. Of the 15 malignancies reported for efalizumab-treated patients, 13 were basal cell (n = 4) or squamous cell (n = 9) carcinomas. Conclusions: These results support the short-term safety profile demonstrated for efalizumab over a longer-term therapy period of up to 60 weeks.

Safety and Tolerability of 60 Weeks' Extended Efalizumab Therapy in Patients with Chronic Moderate to Severe Plaque Psoriasis

The chronic nature of psoriasis calls for long-term maintenance of control; thus, it is important to understand the long-term safety profile of effective therapies. We present long-term safety data for the T-cell inhibitor efalizumab in the treatment of moderate to severe psoriasis. To further assess the safety profile of efalizumab over extended therapy periods, we evaluated pooled results from 1,004 patients enrolled in two studies where patients were to be treated for 60 weeks. The most frequently observed adverse events (AEs) were acute-type AEs, predefined as headache, fever, chills, nausea, vomiting and myalgia occurring within 48 hours of efalizumab dosing. The rate of infection was comparable to rates reported in other efalizumab trials. The most common infections were colds and upper respiratory tract infections. The incidence of malignancy was <1% in any 12-week period. These studies demonstrate that the safety profile for efalizumab is maintained for up to 60 weeks.

Population Pharmacokinetics of Efalizumab (Humanized Monoclonal Anti-CD11a Antibody) Following Weekly Dosing in Psoriasis Patients

Clinical Pharmacology & Therapeutics (2003) 73, P86–P86; doi: