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Pharmacokinetic aspects of biotechnology products

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Abstract

In recent years, biotechnologically derived peptide and protein-based drugs have developed into mainstream therapeutic agents. Peptide and protein drugs now constitute a substantial portion of the compounds under preclinical and clinical development in the global pharmaceutical industry. Pharmacokinetic and exposure/response evaluations for peptide and protein therapeutics are frequently complicated by their similarity to endogenous peptides and proteins as well as protein nutrients. The first challenge frequently comes from a lack of sophistication in various analytical techniques for the quantification of peptide and protein drugs in biological matrices. However, advancements in bioassays and immunoassays—along with a newer generation of mass spectrometry-based techniques—can often provide capabilities for both efficient and reliable detection. Selection of the most appropriate route of administration for biotech drugs requires comprehensive knowledge of their absorption characteristics beyond physicochemical properties, including chemical and metabolic stability at the absorption site, immunoreactivity, passage through biomembranes, and active uptake and exsorption processes. Various distribution properties dictate whether peptide and protein therapeutics can reach optimum target site exposure to exert the intended pharmacological response. This poses a potential problem, especially for large protein drugs, with their typically limited distribution space. Binding phenomena and receptor-mediated cellular uptake may further complicate this issue. Elimination processes—a critical determinant for the drug's systemic exposure—may follow a combination of numerous pathways, including renal and hepatic metabolism routes as well as generalized proteolysis and receptor-mediated endocytosis. Pharmacokinetic/pharmacodynamic (PK/PD) correlations for peptide and protein-based drugs are frequently convoluted by their close interaction with endogenous substances and physiologic regulatory feedback mechanisms. Extensive use of pharmacokinetic and exposure/response concepts in all phases of drug development has in the past been identified as a crucial factor for the success of a scientifically driven, evidence-based, and thus accelerated drug development process. Thus, PK/PD concepts are likely to continue and expand their role as a fundamental factor in the successful development of biotechnologically derived drug products in the future.

Section snippets

INTRODUCTION

In recent years, biotechnologically derived drugs (biotech drugs) including proteins, peptides, monoclonal antibodies, and antibody fragments, as well as antisense oligonucleotides and DNA preparations for gene therapy, have been a major focus of research and development (R&D) efforts in the pharmaceutical industry. According to the PHARMA 2010 report,1 biotech products accounted for more than 35% of the 37 New Active Substances that were launched in 2001. Furthermore, it has been predicted that

ADMINISTRATION PATHWAYS

Peptides and proteins, unlike conventional small molecule drugs, are generally not therapeutically active upon oral administration.24,37,38 This lack of systemic bioavailability is mainly caused by two factors, high gastrointestinal enzyme activity and the function of the gastrointestinal mucosa as an absorption barrier. There is substantial peptidase and protease activity in the gastrointestinal tract, making it the most efficient body compartment for peptide and protein metabolism.

DISTRIBUTION

The volume of distribution of a drug is determined largely by its physiochemical properties (e.g., charge, lipophilicity), protein binding, and its dependency on active transport processes. Much of the studies regarding biodistribution of therapeutic biotech agents are elucidated with radiolabeled compounds. For example, radiolabeled proteins are typically used to assess specific drug targets or major organs of elimination.

Because most of the therapeutic proteins are large in size, their

ELIMINATION

General tendencies in the in vivo disposition of proteins and peptides may often be predicted from their physiological function. Peptides, for example, frequently have hormone activity and usually have short elimination half-lives. This is desirable for a close regulation of their endogenous levels and thus function. Contrary to that, transport proteins like albumin or antibodies have elimination half-lives of several days, which enables and ensures the continuous maintenance of necessary

INTERSPECIES SCALING

In drug development, extrapolation of pharmacokinetic data from animals to humans is frequently necessary, especially at the transition of preclinical to clinical development to predict plasma concentrations in humans and select an appropriate dosage range for first-in-man studies. Allometric scaling is a frequently used tool to make predictions on pharmacokinetic parameters in humans based on data from several animal species, with several approaches available at variable success rates.124.,

EXPOSURE/RESPONSE CORRELATIONS

Pharmacokinetic characteristics and systemic exposure of drugs, conventional small molecule drugs as well as peptides and proteins, are meaningful for applied pharmacotherapy and dosage selection only if they can be related to desired and/or undesired therapeutic outcomes, such as efficacy and/or toxicity. Integrated pharmacokinetic/pharmacodynamic (PK/PD) modeling concepts are a particularly useful tool in the characterization of the frequently complex exposure/response relationships of peptide

CONCLUSION

Peptide and protein drugs are subject to the same general principles of pharmacokinetics and exposure/response correlations as conventional small drug molecules. Due to their similarity to protein nutrients and/or especially regulatory endogenous peptides and proteins, however, numerous caveats and pitfalls related to bioanalytics and pharmacokinetics have to be considered and addressed during their drug development process. Furthermore, PK/PD correlations are frequently complicated due to the

Acknowledgements

Dr. Lisa Tang is partially supported by a Rho Chi Schering-Plough Graduate Scholarship through the American Foundation for Pharmaceutical Education (AFPE).

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