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  • Describe basic classification categories of protein therapeutics and discuss example drugs in each group.

  • Compare and contrast the general pharmacokinetic characteristics of small-molecule and biological drugs.

  • Describe the unique targeting mechanisms of monoclonal antibodies and novel antibody-based constructs along with general determinants of their disposition and effects.

  • Identify the need and rationale for drug carriers and formulations for biologics along with the major components of targeted drug delivery systems.

  • Recognize integrating and non-integrating delivery vectors that address disposition challenges and enable effective gene therapies.

  • Describe the major processes governing the pharmacokinetic properties of biopharmaceuticals.


Early clinical applications of protein therapeutics focused on the replacement of deficient or abnormal protein concentrations, such as insulin in type 1 diabetes mellitus, and relied on the purification of proteins from animal origins. Breakthroughs in molecular biology, recombinant DNA technology, protein engineering, and drug formulations and delivery systems have fueled a revolution in protein-based therapeutics and innovative targeted drug delivery systems. Biological drugs are now a major sector of the pharmaceutical industry, with biologics making up 29% of new drug approvals by the Food and Drug Administration (FDA) in 2018. There are several advantages of biopharmaceuticals over small-molecule drugs, including highly specific mechanisms of action and better tolerability profiles with a decreased potential for adverse drug effects. Small-molecule drugs often cannot mimic the full range of pharmacological effects of protein-based therapeutics, are typically associated with off-target toxicities, and safety and efficacy remain the primary reasons for the attrition of new chemical entities during drug development. In contrast, biotechnological products have tremendous potential for treating disease and can also be incorporated into targeted delivery systems to improve the therapeutic index of potent small-molecule drugs.

The molecular properties and physiological processes that govern the pharmacokinetics of biological drugs are unique from those of small-molecule drugs, and incomplete understanding of the determinants of drug absorption and disposition is a major challenge to the development and utilization of these innovative agents. There is substantial variability in the pharmaco-kinetic properties of biological drugs. Monoclonal antibody and antibody-based drugs tend to exhibit long circulating half-lives as compared to cytokines, peptides, and relatively small proteins owing to an endogenous recycling pathway. Another important factor is target-mediated drug disposition (TMDD), in which interactions of protein-based therapeutics with cell-surface receptors influence the pharmaco-kinetic characteristics of the drug. Numerous drug-specific physicochemical properties also influence the disposition of biologics, including molecular size, charge heterogeneity, hydrophobicity, and other engineered modifications. In contrast to small-molecule drugs, immunogenic reactions to protein therapeutics can also alter their pharmacokinetics and/or pharmacodynamics. This chapter will introduce a diverse array of biotechnology products and targeted delivery systems, highlight the advantages and challenges associated with biological drugs, and review their salient pharmacokinetic properties.


Protein Drugs

The discovery of recombinant DNA technology in the 1970s revolutionized the development of ...

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