Biodistribution of Etanercept to Tissues and Sites of Inflammation in Arthritic Rats

Abstract

Many monoclonal antibodies (mAbs) and other protein drugs have targets usually residing within tissues, making tissue concentrations of mAbs relevant to their pharmacologic effects. Therefore, knowledge of tissue distribution kinetics is important to better understand their pharmacokinetics and pharmacodynamics. The tissue distribution of mAbs is affected by many physiologic factors that may be altered in disease status. In the present work, we studied the tissue distribution kinetics of the fusion protein etanercept in inflamed joint tissues and examined the impact of inflammation on the tissue distribution of etanercept. Etanercept concentration profiles in plasma, blister fluid, and different tissues were obtained from healthy and collagen-induced arthritic (CIA) rats by use of a fluorescence quantification method via IRDye800CW labeling. Stepwise minimal and full physiologically based pharmacokinetic (PBPK) approaches were applied to characterize the distribution kinetics of etanercept in tissues in healthy and diseased animals. Etanercept exhibited modest tissue access (tissue/plasma area under the concentration curve [AUC] ratios 0.03-0.15 and estimated tissue reflection coefficients [s] of 0.6-1.0), but with good penetration into arthritic paws (tissue/ plasma AUC ratio 0.23 and s 0.36). Etanercept exposure in the inflamed paws of CIA rats was approximately 3-fold higher than in normal paws taken from either CIA or healthy rats (tissue/plasma AUC ratios 0.23 versus 0.07 and s 0.36 versus 0.71). The tissue distribution kinetics of etanercept in arthritic paws were well characterized with PBPK modeling approaches. Etanercept shows good penetration to arthritic paws in CIA rats. Our study indicates that inflammation produced increased tissue distribution of etanercept in CIA rats.

Minimal physiologically-based pharmacokinetic (mPBPK) model for a monoclonal antibody against interleukin-6 in mice with collagen-induced arthritis

“…The estimated vascular reflection coefficients ( σ j_ctrl and σ j_CIA ) suggest twofold increase of vascular permeability in CIA mice. This corresponds well with our previous study showing that inflammation causes increased vascular permeability and enhanced tissue distribution of etanercept in arthritic paws in CIA rats [19]. …”

Physiologically‐Based Pharmacokinetic Modeling vs. Allometric Scaling for the Prediction of Infliximab Pharmacokinetics in Pediatric Patients

“…Large molecule drugs abide by permeability‐rate‐limited distribution and are subject to vascular hyperpermeability in inflamed organs. To represent this effect, the pore sizes in inflamed organs were increased proportional to an inflammation factor in agreement with previous minimal PBPK models of inflammatory conditions by other studies that observed the requirement for lower vascular reflection coefficients in inflamed organs. The large intestine was inflamed in patients with inflammatory bowel disease, the bone was inflamed in patients with rheumatoid arthritis and ankylosing spondylitis, the skin was inflamed in patients with psoriasis, and the lungs were inflamed in patients with non‐small cell lung cancer.…”

Assessment of Placental Disposition of Infliximab and Etanercept in Women With Autoimmune Diseases and in the Ex Vivo Perfused Placenta

“…For etanercept, we were able to detect a placental concentration in one patient only, who received etanercept shortly (4 days) before delivery. Tissue distribution of etanercept in rats was found to be 7–15% of plasma levels, depending on the type of tissue 23 . No placental tissue was studied, but the order of magnitude of tissue exposure appears in line with the placental distribution of approximately 3% of the plasma concentration that we report here.…”