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Bernd Meibohm is an Associate Professor of Pharmaceutical Sciences at the College of Pharmacy of the University of Tennessee Health Science Center, Memphis. He obtained his PhD from the University Carolo-Wilhelmina in Braunschweig, Germany, and underwent postdoctoral training in clinical pharmacology at the University of Florida, Gainesville. His research is focused on pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenetics (PG) with special emphasis on PK/PD/PG correlations. Professor Meibohm is a Fellow of the American College of Clinical Pharmacology (ACCP) and has received numerous awards, including the 'Young Investigator Award in PK, PD and Drug Metabolism' from the American Association of Pharmaceutical Scientists (AAPS) in 2000. He is currently serving as Section Editor for PK and PD for the 'Journal of Clinical Pharmacology' and on the Editorial Boards of the 'Journal of Pediatric Pharmacology and Therapeutics' and 'Die Pharmazie'.

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The characterization and optimization of pharmacokinetic properties and exposure-response relationships are crucial parts in the drug development of biotechnologically-derived drug products. Until recently, our understanding of pharmacokinetics and pharmacodynamics was limited to 'traditional' small-molecule, non-biological drugs. Now, with the current boom in drugs based on biological molecules, such as proteins and nucleotides, there is an urgent need to understand the pharmacokinetic and pharmacodynamic characteristics of these very different types of drugs. This book meets that need.
Comprehensive in its coverage, it spans relevant topics from early phase drug development right up to late-stage clinical trials. Following an introduction to the role of PK and PD in the development of biotech drugs, the first section covers the basics, including the pharmacokinetics of peptides, monoclonal antibodies, antisense oligonucleotides, as well as viral and non-viral gene delivery vectors. The second section discusses challenges and opportunities in the pharmaceutical development of biologics, including issues related to bioanalytical assays, bioequivalence and exposure-response assessments, as well as drug delivery. The final section considers the integration of PK and PD concepts into the biotech drug development plan, taking as case studies the preclinical and clinical drug development of tasidotin, as well as the examples set by cetuximab and pegfilgrastim.
Vital reading for all pharmaceutical scientists working with biologics.

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The characterization and optimization of pharmacokinetic properties and exposure-response relationships are crucial parts in the drug development of biotechnologically-derived drug products. Until recently, our understanding of pharmacokinetics and pharmacodynamics was limited to 'traditional' small-molecule, non-biological drugs. Now, with the current boom in drugs based on biological molecules, such as proteins and nucleotides, there is an urgent need to understand the pharmacokinetic and pharmacodynamic characteristics of these very different types of drugs. This book meets that need.
Comprehensive in its coverage, it spans relevant topics from early phase drug development right up to late-stage clinical trials. Following an introduction to the role of PK and PD in the development of biotech drugs, the first section covers the basics, including the pharmacokinetics of peptides, monoclonal antibodies, antisense oligonucleotides, as well as viral and non-viral gene delivery vectors. The second section discusses challenges and opportunities in the pharmaceutical development of biologics, including issues related to bioanalytical assays, bioequivalence and exposure-response assessments, as well as drug delivery. The final section considers the integration of PK and PD concepts into the biotech drug development plan, taking as case studies the preclinical and clinical drug development of tasidotin, as well as the examples set by cetuximab and pegfilgrastim.
Vital reading for all pharmaceutical scientists working with biologics.

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Pharmacokinetics and Pharmacodynamics of Biotech Drugs

John Wiley & Sons

Chapter One

Bernd Meibohm

1.1 Introduction

During the past two decades, advances in biotechnology have triggered the development of numerous new drug products. This group of so-called biotech drugs is a subset of the therapeutic group of biologics. Therapeutic biologic products, or biologics, are defined by the U.S. Food and Drug Administration (FDA) as any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man. Biologics are a subset of drug products distinguished by their manufacturing process. While classical drugs are synthesized via a chemical process, biologics are manufactured utilizing biological processes and are typically derived from living material – human, plant, animal, or microorganism. Biotech drugs can be considered as those biologics that are manufactured using biotechnology-based production processes.

The similarity in the drug development and evaluation process for biotech drugs and conventional, chemically synthesized drugs has recently been acknowledged in the FDA's 2003 decision to transfer certain product oversight responsibilities from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER). The biologics for which oversight was transferred include monoclonal antibodies for in vivo use, proteins intended for therapeutic use, including cytokines (e.g., interferons), enzymes (e.g., thrombolytics), growth factors, and other novel proteins that are derived from plants, animals, or microorganisms, including recombinant versions of these products, and other non-vaccine and non-allergenic therapeutic immunotherapies. Classical biologics such as blood, blood components and vaccines remain under the regulatory authority of the CBER. Even under this new structure, however, the biologic products transferred to the CDER will continue to be regulated as licensed biologics – that is, a Biologic License Application (BLA) must be submitted to obtain marketing authorization as compared to a New Drug Application (NDA) which is used for traditional, chemically manufactured drug products.

For the purpose of this book, biotech drugs include not only therapeutically used peptides and proteins, including monoclonal antibodies, but also oligonucleotides and DNA preparations for gene therapy. Although oligonucleotides are, due to their chemically defined production process, classified by the FDA as classical drugs requiring an NDA prior to marketing authorization, and DNA preparations for gene therapy are regulated by the CBER, they are both included in the class of biotech drugs as their therapeutic application relies heavily on the principles of molecular biology and they are considered by analysts as biotech compounds.

1.2 Biotech Drugs and the Pharmaceutical Industry

In parallel with the development of the discipline of biotechnology during the past two decades, an increasing fraction of pharmaceutical R&D has been devoted to biotechnology-derived drug products. It has been estimated that more than 250 million patients have benefited from already approved biotechnology medicines to treat or prevent heart attacks, stroke, multiple sclerosis, leukemia, hepatitis, rheumatoid arthritis, breast cancer, diabetes, congestive heart failure, kidney cancer, cystic fibrosis and other diseases [1]. This number is expected to increase significantly with the introduction of new biotech drugs into the marketplace. According to a survey by the Pharmaceutical Research and Manufacturers of America (PhRMA) in 2004, 324 biotechnology medicines were in development for almost 150 diseases. These include 154 medicines for cancer, 43 for infectious diseases, 26 for autoimmune diseases, and 17 for AIDS/HIV and related conditions. These potential medicines – all of which were at the time of the survey either in human clinical trials or under review by the FDA – will enlarge the list of 108 biotechnology medicines already approved and available to patients (Fig. 1.1).

Biotech and genomic companies currently perform almost one-fifth of all pharmaceutical R&D, and this figure is set to double during the next 10 years. It has been suggested that over half of all the New Active Substances developed during the next 10–15 years will result from research into antibodies alone. Biotechnology products accounted for more than 35% of the 37 New Active Substances that were launched in 2001. This success in drug development is underlined by the fact that several biotech drugs have achieved blockbuster status, earning more than US$ 1 billion in annual sales, including Epoetin-α (Epogen/Procrit/ Eprex), interferon-α2b (IntronA, PEG-Intron/Rebetron combination therapy), and filgrastim (Neupogen).

Since the development of biotech drugs generally rests on a fundamental understanding of the related disease, their clinical development has also proven to be more successful than for conventional, chemically derived small-molecule drugs. Only 8% of the new chemical entities that entered the clinical phases of drug development between 1996 and 1998 reached the market, compared to 34% of biotech drugs (Fig. 1.2). This means that biologics have, at the time of their first-in4 man studies, a fourfold greater chance than traditional, chemically defined drugs of making it into the marketplace. Thus, greater use of biologics will likely reduce the attrition rate at every stage of the clinical drug development process. Based on these facts, it can be predicted that biotech drugs will play a major – if not dominant – role in the drug development arena of the next decades.

1.3 Pharmacokinetics and Pharmacodynamics in Drug Development

The general paradigm of clinical pharmacology is that administration of a dose or the dosing regimen of a drug results in defined drug concentrations in various body compartments and fluids. These are, in turn, the driving force for the drug's desired and undesired effects on the human body that collectively constitute the drug's efficacy and safety profile. Based on this paradigm, the basis for the pharmacotherapeutic use of biotech drugs is similar to that of small molecules – a defined relationship between the intensity of the therapeutic effect and the amount of drug in the body or, more specifically, the drug concentration at its site of action (i.e., an exposure–response relationship). The relationship between the administered dose of a drug, the resulting concentrations in body fluids and the intensity of produced outcome may be either simple or complex, and thus obvious or hidden. However, if no simple relationship is obvious, it would be misleading to conclude a priori that no relationship exists at all rather than that it is not readily apparent.

The dose–concentration–effect relationship is defined by the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of a drug. Pharmacokinetics comprises all processes that contribute to the time course of drug concentrations in various body fluids, generally blood or plasma – that is, all processes affecting drug absorption, distribution, metabolism, and excretion. In contrast, pharmacodynamics characterizes the effect...