Monoclonal antibodies pharmacokinetics

Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008 84(5) 548-558. 

Rituximab is a monoclonal antibody to the CD20 receptor expressed on the surface of B lymphocytes the presence of the antibody is determined during flow cytometry of the tumor cells. Cell death results from antibody-dependent cellular cytotoxicity. The pharmacokinetics of rituximab are best described by a two-compartment model, with a terminal half-life of 76 hours after the first infusion and a terminal half-life of 205 hours after the fourth dose.36 Rituximab has shown clinical activity in the treatment of B-cell lymphomas that are CD20+. Side effects include hypersensitivity reactions, hypotension, fevers, chills, rash, headache, and mild nausea and vomiting. 

Joshi, A., Bauer, R., Kuebler, P, White, M., Leddy, C., Compton, P., Garovoy, M., Kwon, P., Walicke, P., and Dedrick, R. 2006. An overview of the pharmacokinetics and pharmacodynamics of efalizumab a monoclonal antibody approved for use in psoriasis. Journal of Clinical Pharmacology 46(1), 10-20. 

Ternant D, Paintaud G. Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins. Expert Opin Biol Ther 2005 Suppl 1 837-47. 

Many biopharmaceutical preparations are heterogeneous and may be difficult to fully characterise. Certain fractions of a preparation may have different biological activity or kinetics than the intended product. It is important that such fractions are appropriately qualified. The proportions of these fractions may be altered when production changes are made or they may be different between similar products produced by different manufacturers. Because of their proteinaceous nature and their novel mechanisms of action, all preclinical and clinical development steps must be re-evaluated. For pharmacokinetic studies, blood concentrations should be measured by specific analytical techniques (most often ELISA), which quantify the active protein and not one of its fragments or inactive forms, such as antigen-antibody complexes. For PK-PD studies of monoclonal antibodies, relevant biomarkers are most often circu-... 

Mould DR, Sweeney KR. The pharmacokinetics and pharmacodynamics of monoclonal antibodies - mechanistic modelling applied to drug development. Curr Opin Drug Discov Devel 2007 10(l) 84-96. 

Mechanism of Action A monoclonal antibody that selectively binds to human immunoglobulin E (IgE) preventing it from binding to the surface of mast cells and basophils. Therapeutic Effect Prevents or reduces the number of asthmatic attacks. Pharmacokinetics Absorbed slowly after subcutaneous administration, with peak concentration in 7-8 days. Excreted in the liver, reticuloendothelial system, and endothelial cells. Half-life 26 days. 

Mascelli MA, Zhou H, Sweet R, Getsy J, et al. 2007. Molecular, biologic and pharmacokinetic properties of monoclonal antibodies Impact of these parameters on early clinical development. J Clin Pharmacol. 47 553-565. 

Therapeutic monoclonal antibodies are widely recognized to be a most promising means to treat an increasing number of human diseases, including cancers and autoimmunity. To a large extent, the efficacy of monoclonal antibody treatment is because IgG antibodies have greatly extended persistence in vivo. However, conventional rodent models do not mirror human antibody pharmacokinetics. The key molecule responsible for the extended persistence antibodies is the major histocompatibility complex class I family Fc receptor, FcRn. We describe human FcRn transgenic mouse models and how they can be exploited productively for the preclinical pharmacokinetic evaluation of therapeutic antibodies. 

Key words Monoclonal antibodies, Fc-fusion proteins, FcRn, transgenic mice, pharmacokinetics, serum half-life. 

As of 2008, 25 therapeutic monoclonal antibodies (mAbs) mAbs had been approved for clinical use in the United States, and with over 400 antibodies being in preclinical and clinical development further increase of antibody therapies is assured (10, 11). As a general rule, the Fc fragment is a key component of therapeutic mAb design because it extends their pharmacokinetics. Inclusion of the Fc from IgG is also a key component of other bioactive proteins where prolongation of pharmacokinetics is desired, e.g., the tumor necrosis factor receptor (TNFR) fusion protein etan-ercept (Enbrel ) (12). Thus for both therapeutic antibodies and Fc-fusion proteins, the FcRn interaction is a generalized way to exploit FcRn protection to achieve the benefits of extended persistence in vivo. 

A. Gonsho,Y. Ikeda, and R. Yoshimoto. 2002. Pharmacokinetics and pharmacodynamics of AJW200, a humanized monoclonal antibody to von Willebrand factor, in monkeys. Arterioscler. Thromb. Vase. Biol. 22 187-192. 

Reilly, R.M., J. Sandhu,T.M. Alvarez-Diez, S. Gallinger, J. Kirsh, and H. Stern. 1995. Problems of delivery of monoclonal antibodies. Pharmaceutical and pharmacokinetic solutions. Clin. Pharmacokinet. 28 126-142. 

Table 3.4 Approved dosing regimens and pharmacokinetic parameters related to absorption/bioavailability for therapeutic monoclonal antibodies.

---