Pharmacokinetics and Pharmacodynamics

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Once administered by subcutaneous injection, etanercept is slowly absorbed in both healthy volunteers and in patients with psoriasis, with time to peak serum concentrations in excess of 50 h. In addition, the drug appears to be widely distributed, including in the synovium, and is likely metabolized by proteolytic processes before recycling or elimination in the bile or urine. Elimination half-lives are similar for etanercept in patients with psoriasis and rheumatoid arthritis, with 68 h being seen in healthy volunteers and 102 h in patients with rheumatoid arthritis. In addition, steady-state pharmacokinetic properties of etanercept administered twice weekly are similar to those in patients with rheumatoid arthritis. Lastly, studies examining intermittent and continuous etanercept administration have found no differences in the pharmacokinetic profiles of the two dosing regimes.

Most data on the biological effects of etanercept have been conducted in those patients with rheumatoid arthritis. In this population, etanercept therapy has been found to reduce plasma levels of IL-6 and matrix metalloproteases (MMP), and the immunohistochemi-cal staining of CD3+ T cells, CD 38+ T cells, IL-1ß, and vascular cell adhesion molecule (VCAM). In addition, long-term treatment reduces the numbers of TNF-a and IL-1 producing cells to the numbers seen in healthy controls. Gottlieb and colleagues studied histological response, inflammatory gene expression, and cellular infiltration in psoriatic plaques of patients receiving etanercept, 25 mg subcutaneously twice weekly for 6 months. After 6 months of treatment with etanercept, nine out of the ten patients treated had thinning of the epidermis and normalization of keratinocyte differentiation, and eight of the ten displayed an absence of keratin 10 (K 16), indicating normalization of keratinocyte differentiation and proliferation. A rapid and complete reduction of both IL-1 and IL-8 were observed, with maximal suppression seen by 1 month of treatment. Unlike IL-1 and IL-8, which are early TNF-a induced genes, most other inflammatory genes, such as STAT-1, inducible nitric oxide synthase (iNOS), IL-23, and IP-10 (IFN-y-inducible protein-10, CXCL 10), showed a more gradual response and generally were most suppressed at 6 months. Slower reductions in infiltrating myeloid cells (CD11c+ cells) and T lymphocytes were also observed. In another study, NF-kB, a nuclear transcription factor central in the cell stress response and keratinocyte differentiation, was found to be upregulated in the epidermis of normal epidermis of psoriasis patients, and even more so in the plaques of these patients. Treatment with etanercept correlated with downregulation of phos-phorylated NF-kB as well as decreases in epidermal thickness, return of normal markers of keratinocyte differentiation, and lastly clinical outcomes.

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