Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins.
Although monoclonal antibodies (mAbs) constitute a major advance in therapeutics, their pharmacokinetic (PK) and pharmacodynamic (PD) properties are not fully understood. Saturable mechanisms are thought to occur in distribution and elimination of mAbs, which are protected from degradation by the Brambell's receptor (FcRn). The binding of mAbs to their target antigen explains part of their nonlinear PK and PD properties. The interindividual variability in mAb PK can be explained by several factors, including immune response against the biodrug and differences in the number of antigenic sites. The concentration-effect relationships of mAbs are complex and dependent on their mechanism of action. Interindividual differences in mAb PD can be explained by factors such as genetics and clinical status. PK and concentration-effect studies are necessary to design optimal dosing regimens. Because of their above-mentioned characteristics, the interindividual variability in their dose-response relationships must be studied by PK-PD modelling.
Ternant
David
D
François-Rabelais University, UPRES EA 3853 Immuno-Pharmaco-Genetics of Therapeutic Antibodies, Faculty of Medicine, F 37032 Tours Cedex 1, France.
Paintaud
Gilles
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D001666:Binding Sites, Antibody; D015415:Biomarkers / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D002986:Clinical Trials as Topic; D003424:Crohn Disease / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008954:Models, Biological; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011961:Receptors, Fc / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D015415:Biomarkers; D015704:CD4 Antigens; C496124:FCGR3A protein, human; D011961:Receptors, Fc; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C121870:clenoliximab; D000069283:Rituximab