General

Etanercept binds specifically to tumor necrosis factor (TNF) and blocks its interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of rheumatoid arthritis (RA), polyarticular-course juvenile rheumatoid arthritis (JRA), and ankylosing spondylitis and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of plaque psoriasis. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, psoriatic arthritis, ankylosing spondylitis (AS), and plaque psoriasis.

Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR.

Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind to two TNF molecules. It inhibits the activity of TNF in vitro and has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis. Etanercept inhibits binding of both TNFα and TNFβ (lymphotoxin alpha [LTα]) to cell surface TNFRs, rendering TNF biologically inactive. Cells expressing transmembrane TNF that bind ENBREL® are not lysed in vitro in the presence or absence of complement.

Etanercept can also modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (i.e., E-selectin and to a lesser extent intercellular adhesion molecule-1 [ICAM-1]), serum levels of cytokines (e.g., IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3 or stromelysin).

Pharmacokinetics

After administration of 25 mg of ENBREL® by a single subcutaneous (SC) injection to 25 patients with RA, a mean ± standard deviation half-life of 102 ± 30 hours was observed with a clearance of 160 ± 80 mL/hr. A maximum serum concentration (Cmax) of 1.1 ± 0.6 mcg/mL and time to Cmax of 69 ± 34 hours was observed in these patients following a single 25 mg dose. After 6 months of twice weekly 25 mg doses in these same RA patients, the mean Cmax was 2.4 ± 1.0 mcg/mL (N = 23). Patients exhibited a two- to seven-fold increase in peak serum concentrations and approximately four-fold increase in AUC_{0-72 hr} (range 1 to 17 fold) with repeated dosing. Serum concentrations in patients with RA have not been measured for periods of dosing that exceed 6 months. The pharmacokinetic parameters in patients with plaque psoriasis were similar to those seen in patients with RA.

In another study, serum concentration profiles at steady state were comparable among patients with RA treated with 50 mg ENBREL® once weekly and those treated with 25 mg ENBREL® twice weekly. The mean (± standard deviation) Cmax, Cmin, and partial AUC were 2.4 ± 1.5 mg/L, 1.2 ± 0.7 mg/L, and 297 ± 166 mg•h/L, respectively, for patients treated with 50 mg ENBREL® once weekly (N = 21); and 2.6 ± 1.2 mg/L, 1.4 ± 0.7 mg/L, and 316 ± 135 mg•h/L for patients treated with 25 mg ENBREL® twice weekly (N = 16).

Pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on ENBREL® disposition.

Patients with JRA (ages 4 to 17 years) were administered 0.4 mg/kg of ENBREL® twice weekly for up to 18 weeks. The mean serum concentration after repeated SC dosing was 2.1 mcg/mL, with a range of 0.7 to 4.3 mcg/mL. Limited data suggests that the clearance of ENBREL® is reduced slightly in children ages 4 to 8 years. Population pharmacokinetic analyses predict that administration of 0.8 mg/kg of ENBREL® once weekly will result in Cmax 11% higher, and Cmin 20% lower at steady state as compared to administration of 0.4 mg/kg of ENBREL twice weekly. The predicted pharmacokinetic differences between the regimens in JRA patients are of the same magnitude as the differences observed between twice weekly and weekly regimens in adult RA patients.

CLINICAL STUDIES

Adult Rheumatoid Arthritis

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