AI Article Synopsis

  • Researchers found that monoclonal antibodies (mAbs) with a high isoelectric point (pI) clear quickly from plasma and have a large distribution volume in mice, but existing pharmacokinetic models don't explain this behavior.
  • To improve understanding, they optimized various physiological parameters and developed a new pharmacokinetic model that demonstrated a positive relationship between pI, plasma clearance (CL), and distribution volume (Vdss) in wild-type and FcRn-deficient mice.
  • Their findings suggest that a positive electrostatic interaction between mAbs and endothelial membranes enhances the transcytosis (transport) of mAbs, leading to better distribution in the body and which counters previous models' assumptions.

Article Abstract

We previously reported that monoclonal antibodies (mAbs) with a high isoelectric point (pI) value tended to exhibit fast plasma clearance (CL) and large steady-state volume of distribution (Vdss) in mice. However, the positive correlation between pI, CL, and Vdss cannot be described by the reported physiologically based pharmacokinetic (PBPK) models, in which FcRn-mediated transcytosis of mAbs is set to be minimal compared to convection-mediated transport. To address this issue, physiological parameters (lymph flow rate, reflection coefficient, endothelial uptake clearance, and FcRn concentration) were optimized based on the pharmacokinetic profiles of mAbs with various pI values in wild type and FcRn-deficient (beta-2-microglobulin knockout [KO]) mice. Simulations using the PBPK model developed in this study showed a positive correlation between pI, CL and Vdss observed in wild-type mice. Therefore, this model successfully characterized our hypothetical mechanism that an electrostatic positive interaction between mAbs and the endothelial membrane enhances FcRn-mediated transcytosis of mAbs, resulting in large Vdss. We sought to determine the right contribution of the two pathways of antibody distribution to the interstitial space and established a new model that could effectively capture the effect of pI on FcRn-mediated distribution of mAbs in the body.

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Source
http://dx.doi.org/10.1016/j.dmpk.2023.100506DOI Listing

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