Pharmacokinetics of Monoclonal Antibodies

Abstract

Monoclonal antibodies (mAbs) have developed in the last two decades into the backbone of pharmacotherapeutic interventions in a variety of indications, with currently more than 40 mAbs approved by the US Food and Drug Administration, and several dozens more in clinical development. This tutorial will review major drug disposition processes relevant for mAbs, and will highlight product-specific and patient-specific factors that modulate their pharmacokinetic (PK) behavior and need to be considered for successful clinical therapy.

Figure 1

Monoclonal antibody structure.

Figure 2

Convective extravasation as major distribution process for monoclonal antibodies (modified from ref. 12).

Figure 3

Protection of immunoglobulin G (IgG) molecules from lysosomal degradation by the neonatal fragment crystallizable‐receptor (FcRn) salvage pathway.

Figure 4

Commonly encountered N‐glycan structures in the fragment crystallizable portion of monoclonal antibodies (based on refs. 63 and 64).

Figure 5

Multiple clearance pathways affecting the pharmacokinetics of a monoclonal antibody (mAb). Depicted is a typical two‐compartment PK model for a mAb with administration of a dose (D) that may undergo presystemic degradation (degradation rate constant [k_deg]), concentrations of the mAb in the central (Ab₁) and peripheral (Ab₂) compartment, and interdepartmental clearance (Q). The PK model includes two linear clearance pathways representative of unspecific proteolytic degradation, one from the central compartment (CL₁) and one from the peripheral compartment (CL₂), as well as recycling through the neonatal neonatal fragment crystallizable receptor (FcRn)‐mediated salvage pathway (recycling rate constant (K_rmr)). Added to these clearance pathways is, on the right‐hand side, a target‐mediated disposition pathway that constitutes interaction of the mAb with its pharmacologic target receptor, which is in a homeostatic equilibrium of synthesis and degradation (rate constants k_syn and k_deg). The dynamic equilibrium for the formation of the resulting mAb‐receptor complex (Ab‐R) is determined through the association rate constant k_on and the dissociation rate constant k_off. The formation of Ab‐R not only elicits the pharmacologic effect but also triggers degradation of the complex. Thus, target binding and subsequent Ab‐R degradation constitute an additional clearance pathway for the mAb (CL₃). The left‐hand side of the graphic depicts the effect of an immune response to the mAb resulting in anti‐drug antibody (ADA) formation. Again, the circulating concentration of the ADA is determined by a homeostatic equilibrium between its formation rate (k_formation) and a catabolic turnover process (rate constant (k_cat)). The ADA response results in the formation of immune complexes with the drug (ADA‐Ab), dependent on the dissociation constant K_d. Dependent on the size and structure of the immune complexes, endogenous elimination pathways through the reticuloendothelial system may be triggered, most likely via fragment crystallizable‐gamma (Fcγ)‐mediated endocytosis. Thus, immune complex formation and subsequent degradation may constitute an additional clearance pathway (CL₄) for mAbs (modified from ref. 97; reproduced with permission of Springer).