Absorption

Etanercept is slowly absorbed after subcutaneous injection, with peak serum concentrations being achieved about 50-70 h after single-dose administration (Zhou 2005). Studies have consistently indicated that the mean percentage of etanercept available to the target tissues (the absolute bioavailability) after subcutaneous administration is 58-63% (Zhou 2005). Administering a single 25-mg dose subcutaneously to healthy individuals resulted in a mean peak concentration of 1.5 mg/l at 51 h. A similar dosage administered

Table 4.1. Summarizing table

Structure Receptor fusion protein (ligand-binding portion ofTNF p75 receptor linked to the Fc region oflgGl)

Mechanism of action Binds to soluble or membrane-bound TNF-a

Pharmacodynamics Modulates biological responses mediated by TNF-a, including expression of adhesion molecules important for leukocyte migration, and serum levels of other cytokines and matrix metalloproteinase

Pharmacokinetics

Single dose (25 mg) Cmax (mean ± SD) tmax (mean ± SD) Multiple dosing (25 mg twice weekly) Cmax (mean ± SD) tmax (mean ± SD) Multiple dosing (50 mg once weekly) Cmax (mean ± SD)

Mean absolute bioavailability Half-life

Indications (dosage)a

Healthy individuals

Patients with rheumatoid arthritis

2.8 ±0.8 days (single 25-mg dose) 4.3 ± 1.3 days (25 mg BIW)

Active rheumatoid arthritis (alone or with MTX) in adults with an inadequate response to DMARDs, including MTX, and for severe, active, and progressive rheumatoid arthritis in adults not previously treated with MTX (25 mg twice weekly or 50 mg once weekly)

Active polyarticular-course juvenile chronic arthritis in children aged 4-17 years with an inadequate response to, or intolerance of, MTX (0.4 mg/kg, up to 25 mg per dose, twice weekly) Active and progressive psoriatic arthritis in adults with an inadequate response to DMARD therapy (25 mg twice weekly)

Severe active ankylosing spondylitis in adults with an inadequate response to conventional therapy (25 mg twice weekly)

Moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant of, other systemic therapy, including methotrexate, cyclosporine, or psoralen plus ultraviolet A phototherapy (25 mg twice weekly for up to 24 weeks; 50 mg twice weekly may be used for up to 12 weeks followed, if necessary, by 25 mg twice weekly, for up to 24 total)

a Indications approved by the European Medicines Agency, valid as of date of publication

BIW twice weekly, Cmax peak concentration, DMARD disease-modifying antirheumatic drug, IgGl immunoglobulin G1, MTX methotrexate, SD standard deviation, tmax time to peak concentration, TNF tumor necrosis factor to patients with rheumatoid arthritis achieved a mean peak concentration of 1.1 mg/l at 69 h.

With multiple weekly dosing, etanercept achieves a smooth and uniform steady-state concentration-time profile that is linearly proportional to the weekly dosage administered (Nestorov 2005). The absorption profile of etanercept is similar in patients with rheumatoid arthritis, ankylosing spondylitis, and psoriasis (Nesto-rov et al. 2004; Zhou et al. 2004b). At the end of 24 weeks' treatment with etanercept 25 mg subcutane-ously twice weekly, patients with rheumatoid arthritis achieved a mean peak concentration of 2.4 mg/l at 32 h after the last dose (Zhou 2005). In patients with rheumatoid arthritis, the steady-state pharmacokinetic profiles of etanercept 50 mg once weekly and etanercept

25 mg twice weekly are similar in terms of peak concentration (2.4 vs 2.6 mg/l), trough concentration (1.2 vs 1.4 mg/l), and partial area under the concentration-time curve (297 vs 316 mg h/l) (European Medicines Agency 2005; Enbrel: US Full Prescribing Information 2006). Pharmacokinetic modeling of steady-state trough concentrations of etanercept 25 mg twice weekly was similar for rheumatoid arthritis and ankylosing spondylitis patients (2.1 vs 2.0 mg/l, respectively) (Zhou et al. 2004b). In addition, steady-state pharmacokinetic parameters for etanercept 25 mg twice weekly were similar in rheumatoid arthritis and psoriasis patients, respectively, in terms of peak concentration (2.6 vs 2.5 mg/l), trough concentration (1.4 vs 1.5 mg/l), time to peak concentration (62 vs 61 h), and area under the concentration-time curve (316 vs 321 mg h/l) (Nestorov et al. 2004).

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