Biotechnology: Pharmaceutical Aspects – serie

Drug discovery and development is a very complex, costly, and ti- consuming process. Because of the uncertainties associated with predicting the pharmacological effects and the toxicity characteristics of new chemical entities in man, their clinical development is quite prone to failure. In recent years, phar- ceutical companies have come under increasing pressure to introduce new blockbuster drugs into the marketplace more rapidly. Companies have responded to these pressures by introducing new technologies and new strategies to expedite drug discovery and development. Drug discovery and development have traditionally been divided into three separate processes (i. e. , discovery research, preclinical development, and clinical development) that ideally should be integrated both organizationally and functionally. Instead, separate and distinct discovery research, preclinical development, and clinical development divisions were created within many companies during the 1980s and 1990s, Because of their isolation, scientists in the discovery research divisions often were advancing drug candidates into preclinical development that had marginal drug-like properties. For the purpose of this presentation, “drug-like” properties refer to the molecule’s physicochemical, absorption-distribution-metabolism-excretion (ADME), and toxicological properties. Lacking optimal drug-like properties often caused these drug candidates to fail in preclinical or clinical development.

Prodrugs are substances administered in an inactive form that is then metabolized in the body in vivo into the active compound. The rationale behind administering prodrugs is to optimize absorption, distribution, metabolism, and excretion of these drugs. Since first described in the 1950s, prodrugs continue to be a fertile area of research. There are a number of small pharmaceutical/biotech companies dedicated to using prodrugs for the delivery of older but problematic drugs as well as to developing broad-based prodrug technologies for application to new and future drugs. These volumes represent a comprehensive guide to prodrugs and will guide the reader through the current status of the prodrug concept and its many applications and to highlight its many successes in overcoming formulation and delivery of problematic drugs.

Solvent systems are integral to drug development and pharmaceutical technology. This single topic encompasses numerous allied subjects running the gamut from recrystallization solvents to biorelevant media. The goal of this contribution to the AAPS Biotechnology: Pharmaceutical Aspects series is to generate both a practical handbook as well as a reference allowing the reader to make effective decisions concerning the use of solvents and solvent systems. To this end, the monograph was created by inviting recognized experts from a number of fields to author relevant sections. Specifically, 15 chapters have been designed covering the theoretical background of solubility, the effect of ionic equilibria and pH on solubilization, the use of solvents to effect drug substance crystallization and polymorph selection, the use of solvent systems in high throughput screening and early discovery, solvent use in preformulation, the use of solvents in bio-relevant dissolution and permeation experiments, solvents and their use as toxicology vehicles, solubilizing media and excipients in oral and parenteral formulation development, specialized vehicles for protein formulation and solvent systems for topical and pulmonary drug administration. The chapters are organized such that useful decision trees are included together with the scientific underpinning for their application. In addition, trends in the use of solvent systems and a balance of current views make this monograph useful to both the novice and experienced researcher and to scientists at all developmental stages from early discovery to late pharmaceutical operations.

In the last 15 years, a great number of cell- or tissue-based in vitro models have been introduced into the biopharmaceutics arena. These models mimic the different biological barriers that a drug has to overcome to finally reach its target organ/cell/receptor. These in vitro models have been found very useful in not only characterising the permeability behaviour of drugs molecules in epithelial and endothelial tissues, but also studying drug delivery systems for improved delivery and enhanced absorption. Compared to the complex in vivo situation, in vitro models offer a fast, convenient approach with cost advantages most of times. Most importantly, they can be standardised and automatised to be applicable to the high-throughput screening.Starting at the molecular level of studies, continuing with cell monolayer models (both primary and cell lines) and in situ techniques as a final testing format, the book provides a practical approach to contemporary in vitro techniques for drug absorption studies. In addition, chapters on high-throughput assays, in vitro-in vivo correlation, bioinformatics and regulatory issues are covered, giving a comprehensive overview of available models and techniques. Moreover, an appendix comprised with a number of practical protocols is  available online, updated as needed, should prove very helpful to apply the techniques directly to the benchside.

A particular issue for biopharmaceuticals that has not been addressed comprehensively in any book, is the potential of an immune response to the biopharmaceutical product. That is, the human body marks the drug as a foreign body, and develops antibodies against the drug. These antibodies may be relatively harmless, but may also cross-react with the endogenous compound, causing autoimmunogenicity. Recent adverse experiences in Europe with Janssen-Ortho’s blockbuster product Eprex has increased the attention towards potential immunogenicity of biopharmaceuticals, above all from the regulatory agencies.This book is intended to give a broad overview of the current state-of-the-art regarding the immune response to biopharmaceuticals. The chapters range from an overview of the immune system and factors that may trigger the immune system, via detection of antibodies and clinical implications, to various case examples and the regulatory view on immunogenicity.

Monoclonal antibodies represent one of the fastest growing areas of new drug development within the pharmaceutical industry. Several blockbuster products have been approved over the past several years including Rituxan, Remicade, Avastin, Humira, and Herceptin. In addition, over 300 new drugs are currently in clinical trials. With both large, established biotechnology companies and small start-ups involved in the development of this important class of molecules, monoclonal antibodies products will become increasingly prevalent over the next decade.Recently the regulatory review of monoclonal antibodies has been moved from Center for Biologics and Research to the Center for Drug Evaluation and Research (CDER) division of the US Food and Drug Administration. It is anticipated that CDER will expect a certain minimal amount of data to be provided as more of these products move through the regulatory pipeline. Current Trends in Monoclonal Antibody Development and Manufacturing will provide readers with an understanding of what is currently being done in the industry to develop, manufacture, and release monoclonal antibody products and what will be required for a successful regulatory submission.

I have always been interested in chemistry and biology. My undergraduate, graduate, and postdoctoral trainings in pharmacy, medicinal chemistry and pharmacology, respectively, have strengthened this interest and led me to realize that significant advances in medicine have frequently been realized because of research at the chem- try–biology interface. I am hoping that this comprehensive volume on recent advances in bioactivation research will stimulate pharmacologists, medicinal chemists, phar- ceutical scientists, and graduate students in these fields and related areas to consider and use bioactivation research when they explore and chart new frontiers in drug design and drug development and when they consider ways to reduce the side effects of existing drugs by making prodrugs. As for the toxicologists and environmental health scientists, I hope this volume will help them generate the knowledge needed to understand better mechanisms of toxicity to improve human risk assessments and intervention methods after occupational or environmental exposure to various hazardous chemicals. Adnan A. Elfarra, Ph. D. vii Part I General Concepts and Basic Mechanisms 1 Metabolic Concerns in Drug Design Jeffrey P. Jones Department of Chemistry, Washington State University, Pullman, WA 99164, USA e-mail: jpj@wsu. edu Keywords: Cytochrome P450 Aldehyde Oxidase Drug–Drug Interactions Mechanism-based Virtual Screening ADMET Regioselectivity 1. 1. Introduction Due to recent technological innovations, such as genomics, combinatorial chemistry, and high-throughput screening, the identification of disease targets and of compounds that are active against these targets (‘‘leads’’) can now be carried out efficiently.

The reader will be introduced to various aspects of the fundamentals of nanotechnology based drug delivery systems and the application of these systems for the delivery of small molecules, proteins, peptides, oligonucleotides and genes. How these systems overcome challenges offered by biological barriers to drug absorption and drug targeting will also be described.

Protein pharmaceuticals form a fast-growing category in the arsenal of drugs. In the coming years, the patents on a number of the first-generation protein pharmaceuticals will expire, opening the door for the development of biogenerics into the market. However, it is very difficult to characterize these compounds so that the results can be replicated in a generic form. This volume details the nature of the different analytical techniques and how they are relevant for characterizing pharmaceutical proteins. In addition to serving the analytical chemist, this book is needed by the formulation scientist who is responsible for design and formulation of a pharmaceutical protein that can be monitored during production and over time. It also will be useful for students, fellows, and research scientists who are working in the academic world and in the pharmaceutical/biotechnology industry on basic aspects of proteins.

At a time when pharmaceutical companies have limited resources to develop newer and better drugs, they must continually evaluate the effectiveness and efficiency of their research and development process. This volume focuses on how to increase the efficiency of drug discovery and development. Written by experienced discovery scientists from diverse disciplines, including chemistry, drug metabolism, and development sciences, it details in silico, in vitro, and in vivo tools for prediction, measurement, and application of compound properties to select and improve potential drug candidates.

The International Conference of Harmonization (ICH) has worked on har- nizing the stability regulations in the US, Europe, and Japan since the early 1990s. Even though the Stability Guidelines Q1A (R2) was issued over a decade ago, issues surrounding this arena continue to surface as the principles described in the guideline are applied to different technical concentrations. As a result, the stability community has continued to discuss concerns and find ways of harmonizing regulatory requirements, streamlining practices, improving processes in order to bring safe and effective medical supplies to the patients around the world. In 2007, the American Association of Pharmaceutical Scientists (AAPS) Stability Focus Group organized two workshops – the Stability Workshop and the Degradation Mechanism Workshop. These meetings attracted many industry scientists as well as representatives from several regulatory agencies in the world to discuss important topics related to pharmaceutical stability practices. Recognizing the importance of documenting these discussions and with the permission of AAPS, I have worked with speakers to assemble a collection of 30 articles from presentations given at these two meetings, mainly the Stability Workshop. I trust that this book will be beneficial to all of you in providing guidance and up-to-date information for building quality stability programs. v Freedom of our mind is Mother of all inventions.

Solvent systems are integral to drug development and pharmaceutical technology. This single topic encompasses numerous allied subjects running the gamut from recrystallization solvents to biorelevant media. The goal of this contribution to the AAPS Biotechnology: Pharmaceutical Aspects series is to generate both a practical handbook as well as a reference allowing the reader to make effective decisions concerning the use of solvents and solvent systems. To this end, the monograph was created by inviting recognized experts from a number of fields to author relevant sections. Specifically, 15 chapters have been designed covering the theoretical background of solubility, the effect of ionic equilibria and pH on solubilization, the use of solvents to effect drug substance crystallization and polymorph selection, the use of solvent systems in high throughput screening and early discovery, solvent use in preformulation, the use of solvents in bio-relevant dissolution and permeation experiments, solvents and their use as toxicology vehicles, solubilizing media and excipients in oral and parenteral formulation development, specialized vehicles for protein formulation and solvent systems for topical and pulmonary drug administration. The chapters are organized such that useful decision trees are included together with the scientific underpinning for their application. In addition, trends in the use of solvent systems and a balance of current views make this monograph useful to both the novice and experienced researcher and to scientists at all developmental stages from early discovery to late pharmaceutical operations.

A particular issue for biopharmaceuticals that has not been addressed comprehensively in any book, is the potential of an immune response to the biopharmaceutical product. That is, the human body marks the drug as a foreign body, and develops antibodies against the drug. These antibodies may be relatively harmless, but may also cross-react with the endogenous compound, causing autoimmunogenicity. Recent adverse experiences in Europe with Janssen-Ortho’s blockbuster product Eprex has increased the attention towards potential immunogenicity of biopharmaceuticals, above all from the regulatory agencies.This book is intended to give a broad overview of the current state-of-the-art regarding the immune response to biopharmaceuticals. The chapters range from an overview of the immune system and factors that may trigger the immune system, via detection of antibodies and clinical implications, to various case examples and the regulatory view on immunogenicity.

The reader will be introduced to various aspects of the fundamentals of nanotechnology based drug delivery systems and the application of these systems for the delivery of small molecules, proteins, peptides, oligonucleotides and genes. How these systems overcome challenges offered by biological barriers to drug absorption and drug targeting will also be described.

Monoclonal antibodies represent one of the fastest growing areas of new drug development within the pharmaceutical industry. Several blockbuster products have been approved over the past several years including Rituxan, Remicade, Avastin, Humira, and Herceptin. In addition, over 300 new drugs are currently in clinical trials. With both large, established biotechnology companies and small start-ups involved in the development of this important class of molecules, monoclonal antibodies products will become increasingly prevalent over the next decade.Recently the regulatory review of monoclonal antibodies has been moved from Center for Biologics and Research to the Center for Drug Evaluation and Research (CDER) division of the US Food and Drug Administration. It is anticipated that CDER will expect a certain minimal amount of data to be provided as more of these products move through the regulatory pipeline. Current Trends in Monoclonal Antibody Development and Manufacturing will provide readers with an understanding of what is currently being done in the industry to develop, manufacture, and release monoclonal antibody products and what will be required for a successful regulatory submission.

The International Conference of Harmonization (ICH) has worked on har- nizing the stability regulations in the US, Europe, and Japan since the early 1990s. Even though the Stability Guidelines Q1A (R2) was issued over a decade ago, issues surrounding this arena continue to surface as the principles described in the guideline are applied to different technical concentrations. As a result, the stability community has continued to discuss concerns and find ways of harmonizing regulatory requirements, streamlining practices, improving processes in order to bring safe and effective medical supplies to the patients around the world. In 2007, the American Association of Pharmaceutical Scientists (AAPS) Stability Focus Group organized two workshops – the Stability Workshop and the Degradation Mechanism Workshop. These meetings attracted many industry scientists as well as representatives from several regulatory agencies in the world to discuss important topics related to pharmaceutical stability practices. Recognizing the importance of documenting these discussions and with the permission of AAPS, I have worked with speakers to assemble a collection of 30 articles from presentations given at these two meetings, mainly the Stability Workshop. I trust that this book will be beneficial to all of you in providing guidance and up-to-date information for building quality stability programs. v Freedom of our mind is Mother of all inventions.

In the last 15 years, a great number of cell- or tissue-based in vitro models have been introduced into the biopharmaceutics arena. These models mimic the different biological barriers that a drug has to overcome to finally reach its target organ/cell/receptor. These in vitro models have been found very useful in not only characterising the permeability behaviour of drugs molecules in epithelial and endothelial tissues, but also studying drug delivery systems for improved delivery and enhanced absorption. Compared to the complex in vivo situation, in vitro models offer a fast, convenient approach with cost advantages most of times. Most importantly, they can be standardised and automatised to be applicable to the high-throughput screening.Starting at the molecular level of studies, continuing with cell monolayer models (both primary and cell lines) and in situ techniques as a final testing format, the book provides a practical approach to contemporary in vitro techniques for drug absorption studies. In addition, chapters on high-throughput assays, in vitro-in vivo correlation, bioinformatics and regulatory issues are covered, giving a comprehensive overview of available models and techniques. Moreover, an appendix comprised with a number of practical protocols is  available online, updated as needed, should prove very helpful to apply the techniques directly to the benchside.

I have always been interested in chemistry and biology. My undergraduate, graduate, and postdoctoral trainings in pharmacy, medicinal chemistry and pharmacology, respectively, have strengthened this interest and led me to realize that significant advances in medicine have frequently been realized because of research at the chem- try–biology interface. I am hoping that this comprehensive volume on recent advances in bioactivation research will stimulate pharmacologists, medicinal chemists, phar- ceutical scientists, and graduate students in these fields and related areas to consider and use bioactivation research when they explore and chart new frontiers in drug design and drug development and when they consider ways to reduce the side effects of existing drugs by making prodrugs. As for the toxicologists and environmental health scientists, I hope this volume will help them generate the knowledge needed to understand better mechanisms of toxicity to improve human risk assessments and intervention methods after occupational or environmental exposure to various hazardous chemicals. Adnan A. Elfarra, Ph. D. vii Part I General Concepts and Basic Mechanisms 1 Metabolic Concerns in Drug Design Jeffrey P. Jones Department of Chemistry, Washington State University, Pullman, WA 99164, USA e-mail: jpj@wsu. edu Keywords: Cytochrome P450 Aldehyde Oxidase Drug–Drug Interactions Mechanism-based Virtual Screening ADMET Regioselectivity 1. 1. Introduction Due to recent technological innovations, such as genomics, combinatorial chemistry, and high-throughput screening, the identification of disease targets and of compounds that are active against these targets (‘‘leads’’) can now be carried out efficiently.

Drug discovery and development is a very complex, costly, and ti- consuming process. Because of the uncertainties associated with predicting the pharmacological effects and the toxicity characteristics of new chemical entities in man, their clinical development is quite prone to failure. In recent years, phar- ceutical companies have come under increasing pressure to introduce new blockbuster drugs into the marketplace more rapidly. Companies have responded to these pressures by introducing new technologies and new strategies to expedite drug discovery and development. Drug discovery and development have traditionally been divided into three separate processes (i. e. , discovery research, preclinical development, and clinical development) that ideally should be integrated both organizationally and functionally. Instead, separate and distinct discovery research, preclinical development, and clinical development divisions were created within many companies during the 1980s and 1990s, Because of their isolation, scientists in the discovery research divisions often were advancing drug candidates into preclinical development that had marginal drug-like properties. For the purpose of this presentation, “drug-like” properties refer to the molecule’s physicochemical, absorption-distribution-metabolism-excretion (ADME), and toxicological properties. Lacking optimal drug-like properties often caused these drug candidates to fail in preclinical or clinical development.