Etveza Mechanism of Action

Pharmacotherapeutic Group: Immunosuppressants. Tumour Necrosis Factor alpha (TNF-α) inhibitors.
Pharmacology: Pharmacodynamics: Tumour necrosis factor (TNF) is a dominant cytokine in the inflammatory process of rheumatoid arthritis. Elevated levels of TNF are also found in the synovium and psoriatic plaques of patients with psoriatic arthritis and in serum and synovial tissue of patients with ankylosing spondylitis. In plaque psoriasis, infiltration by inflammatory cells, including T-cells, leads to increased TNF levels in psoriatic lesions compared with levels in uninvolved skin. Etanercept is a competitive inhibitor of TNF binding to its cell surface receptors, and thereby inhibits the biological activity of TNF. TNF and lymphotoxin are pro-inflammatory cytokines that bind to two distinct cell surface receptors: the 55-kilodalton (p55) and 75-kilodalton (p75) tumour necrosis factor receptors (TNFRs). Both TNFRs exist naturally in membrane-bound and soluble forms. Soluble TNFRs are thought to regulate TNF biological activity.
TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on cross-linking of cell surface TNFRs. Dimeric soluble receptors, such as etanercept, possess a higher affinity for TNF than monomeric receptors and are considerably more potent competitive inhibitors of TNF binding to its cellular receptors. In addition, use of an immunoglobulin Fc region as a fusion element in the construction of a dimeric receptor imparts a longer serum half-life.
Mechanism of action: Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin pathology in plaque psoriasis is mediated by pro-inflammatory molecules that are linked in a network controlled by TNF. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF binding to cell surface TNFR, preventing TNF-mediated cellular responses by rendering TNF biologically inactive. Etanercept may also modulate biologic responses controlled by additional downstream molecules (e.g., cytokines, adhesion molecules, or proteinases) that are induced or regulated by TNF.
Pharmacokinetics: The clinical study results indicated rh TNFR: FC was absorbed slowly at injection site after subcutaneous injection. The peak blood concentration achieved at 48 hours after single administration, the absolute bioavailability was 76%. After administered twice weekly, the blood concentration at steady state was two times of the peak concentration of single dose.
11 active RA patients were injected with Yisaipu 25mg subcutaneously twice a week for consecutive 6 weeks, the time to steady state for rhTNFR:FC was 480±20h, Cmax(ss) was 3.0±0.2μg/ml, Cmin(ss) was 2.6±0.2μg/ml, the mean Css was 2.8±0.3μg/ml, the fluctuation index (FI) was 12.8±3.3%. After the last administration of rhTNFR:Fc, T1/2 was 74±4h, Tmax was 53±6h and CL was 102.8±10.4 ml/h.
No significant difference in blood concentration was observed among healthy persons, patients with acute renal failure and patients with abnormal liver functions, therefore, the dose does not need to be adjusted for the patients with renal function impairment. The influence of MTX on the pharmacokinetics of rhTNFR:Fc was not observed in the previously mentioned studies.