Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins

Abstract

There are many factors that can influence the pharmacokinetics (PK) of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediated recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic antibodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation. Glycosylation of a mAb or Fc-fusion protein can have a significant impact on the PK of these molecules. mAb charge can be important and variants with pI values of 1–2 unit difference are likely to impact PK with lower pI values being favorable for a longer half-life. Most mAbs display target mediated drug disposition (TMDD), which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody (ADA) response and off-target binding, which require careful consideration during the discovery stage. mAbs are primarily absorbed through the lymphatics via convection and can be conveniently administered by the subcutaneous (sc) route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be reasonably estimated using cynomolgus monkey data and allometric scaling methods.

Time‐Varying Clearance and Impact of Disease State on the Pharmacokinetics of Avelumab in Merkel Cell Carcinoma and Urothelial Carcinoma

“…The neonatal Fc receptor facilitates IgG recycling and albumin homeostasis, protecting IgG (as well as antibody drugs) from catabolism. Hypoalbuminemia could be a marker for elevated neonatal Fc receptor–mediated protein turnover, resulting in higher CL and lower exposure . In addition, both albumin and C‐reactive protein are markers of baseline inflammation status, and their associations with CL at baseline (negative and positive, respectively) are therefore not surprising in the context of the proposed reasons for time‐varying CL, as discussed previously.…”

Use of Population Pharmacokinetic Analyses Among FDA‐Approved Biologics

“…Fc‐fusion proteins have been developed to achieve a longer half‐life through an FcRn‐mediated immunoglobulin G (IgG) recycling pathway. Therefore, the PK characteristics of Fc‐fusion proteins are expected to be comparable with those of monoclonal antibodies with an Fc region except for the portion of target‐mediated drug disposition . All 6 Fc‐fusion proteins we examined had 2‐compartment models with first‐order linear elimination in their population PK analyses, which was the most common model structure of monoclonal antibody.…”

Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc‐fused interleukin‐1 receptor antagonist, in healthy subjects: A first‐in‐human study

“…The serum concentrations of HL2351 increased dose‐proportionally after single SC administration at up to 12 mg/kg. This is rather unexpected, but is beneficial, given that many therapeutic monoclonal antibodies and Fc‐fusion proteins show nonlinear PK characteristics due to various reasons such as target‐mediated drug disposition elimination, patients' inflammatory status, and immunogenicity . One possible explanation is that soluble receptors (e.g.…”

“…This is rather unexpected, but is beneficial, given that many therapeutic monoclonal antibodies and Fc-fusion proteins show nonlinear PK characteristics due to various reasons such as target-mediated drug disposition elimination, patients' inflammatory status, and immunogenicity. 25,26 One possible explanation is that soluble receptors (e.g. IL-1 receptor) targeting monoclonal antibodies tend to exhibit linear PK characteristics, 27 whereas cell-surface antigen targeting monoclonal antibodies often exhibit target-mediated drug disposition eliminations.…”