bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac SarcolemmalATP‐Sensitive Potassium Channel Antagonists: Novel Ischemia‐Selective Antiarrhythmic Agents
Authors: Billman George E.
Published: March 2010

The activation of cardiac cell membrane ATP‐sensitive potassium channels during myocardial ischemia promotes potassium efflux, reductions in action potential duration, and inhomogeneities in repolarization, thereby creating a substrate for reentrant arrhythmias. Antiarrhythmic drugs inhibit ATP‐sensitive potassium channels at therapeutic concentrations. This article discusses the relationship between ischemically induced alterations in extracellular potassium and arrhythmia formation and evaluates the antiarrhythmic potential of ATP‐sensitive potassium channel antagonists, drugs that may act selectively on the ischemic myocardium.
Herbal Medicines and Animal Models of Gastrointestinal Diseases
Authors: Cho C.H. , Ko J.K.S.
Published: March 2010

Animal models of gastric and duodenal ulcers play important roles in the study of the pathogenesis of gastrointestinal (GI) diseases and in the testing of antiulcer agents. They provide essential tools to screen herbal medicines for their antiulcer and anticancer effects. This article focuses on three major types of chemical compounds from various kinds of herbs and their implications for different GI disorders.
Endocrine and Metabolic Agents
Authors: Furman Brian L.
Published: March 2010

Hormones regulate the secretory and gametogenic functions of the ovaries and testes. Several peptide hormones are synthesized in the hypothalamus. Hypothalamus hormones have a key role in the regulation of the secretory activity of the anterior pituitary. This article focuses on the properties of endocrine hormones, their receptors, hormone analogs acting as agonists and antagonists, and their potential therapeutic applications.
Protein–Protein Interactions
Authors: Kaur Kamaljit , Das Dipankar , Suresh Mavanur R.
Published: March 2010

Protein–protein interactions are key to several biological pathways and thus are attractive targets for therapeutic intervention. Such approaches are based on a sound assessment of the strong and weak interactions and the protein's secondary or tertiary structures. This article focuses on interactions between some of the important protein–protein pairs and recent successes in developing peptides, peptidomimetics, or small organic molecules as inhibitors of these interactions.
Analytical Chemistry Methods: Developments and Validation
Authors: Kapetanovic Izet M. , Lyubimov Alexander V.
Published: March 2010

Analytical methodology plays an integral part of drug development from the initial synthesis and manufacture through clinical trials and postmarketing monitoring. Selection of analytical chemical method to be used should be based on the nature of the analyte(s), analytical goals (sensitivity, selectivity, etc.), sample matrix, and sample stability. This article focuses on development and validation of analytical chemical methods.
How and Where are Drugs Absorbed?
Authors: Bermejo Marival , Gonzalez‐Alvarez Isabel
Published: March 2010

A drug must interact with its receptors at their action sites or therapeutic target to exert its pharmacological or toxic effects. Therefore, the absorption of drug is an essential step which determines pharmacologic effects of drug. This article focuses on the biological barriers that the drug must cross in order to enter the body, drug absorption mechanisms, and influence of physiological characteristics of the administration route on absorption rate and extent.
Stability: Physical and Chemical
Authors: Gorman Eric M. , Padden Brian E. , Munson Eric J.
Published: March 2010

The pharmaceutical properties of a drug, such as solubility, dissolution, and toxicology, can change dramatically when a drug undergoes chemical or physical degradation, limiting the drug's efficacy and safety. Therefore, the evaluation of drug stability becomes part of the development process as early as candidate selection and continues for the lifetime of the product. This article focuses on drug stability up to and through the formulation process.
Dosage Formulation
Authors: Lyubimov Alexander V.
Published: March 2010

Drug formulation aims to determine experimentally all the variables necessary to develop an optimal formula and working directions for making the pharmaceutical product. Pharmaceutical technology applied to developing a drug formulation comprises selection of materials and procedures that are adaptable to various processes that lend themselves to inclusion in specific dosage forms. This article focuses on new dosage formulations, their function and characterization, absorption mechanisms, and novel routes of delivery.
CytochromeP450 Enzymes
Authors: Hrycay Eugene G. , Bandiera Stelvio M.
Published: March 2010

The cytochrome P450 (CYP) enzymes, also known as the microsomal mixed function oxidase system, are the predominant biotransformation pathway in the body for lipid‐soluble endogenous and xenobiotic compounds. CYP enzymes play a key role in the biotransformation of pharmaceutical agents and thus are major determinants of duration of action and clearance of drugs. This article focuses on the characterization, function, and regulation of CYP enzymes that are relevant to our understanding of how CYP enzymes can metabolize a large variety of drugs.
Metabolism Kinetics
Authors: Locuson Charles W. , Tracy Timothy S.
Published: March 2010

Generally, kinetic models are applied toin vitrodata to determine parameters, such as intrinsic clearance to make correlations to thein vivosituation. However, it is increasingly being recognized that these “typical kinetic” conditions may not exist and “atypical kinetics” may be observed, resulting in misestimation of intrinsic clearance. This article focuses on typical and atypical kinetics in drug metabolism reactions.
Drug Clearance
Authors: Panuganti Sree D. , Svensson Craig K.
Published: March 2010

The clearance of a drug candidate is the primary factor in determining the bioavailability, dosing frequency, duration of action, and viable routes of administration for the clinical use of the compound. Thus, the rate and routes of drug clearance can be critical in determining whether or not the development of a candidate compound should move forward. This article provides an overview on clearance concepts, ranging from a description of the routes by which drugs are cleared from the body to pathophysiological conditions that may alter these processes qualitatively and quantitatively.
Utilization ofIn VitroCytochromeP450 Inhibition Data for Projecting Clinical Drug–Drug Interactions
Authors: Kenny Jane R. , McGinnity Dermot F. , Grime Ken , Riley Robert J.
Published: March 2010

The CYP family of enzymes are the primary facilitators of oxidative biotransformation in the liver and are responsible for the metabolism of the majority of human drugs. The CYP family metabolize a very broad range of substrates and play a central role in the mediation of clinically relevant drug–drug interactions (DDIs). This article summarizes the current knowledge base and the complexities of CYP inhibition and provides a guide for embarking on prediction of clinical DDIs with particular emphasis on the drug discovery setting.
Metabolite Profiling and Structural Identification
Authors: Moghaddam Mehran F.
Published: March 2010

Metabolite profiling refers to the process of identifying all drug related metabolites generated through biotransformation reactions in animals or inin vitrosystems. In animals, this process may result in the presence of metabolites in the circulation and in any and all tissues as well as the excreta, collectively referred to as animal matrices. This article provides useful information regarding drug metabolite identification and profiling.
Allometric Scaling
Authors: Hayton William L. , Hu Teh‐Min
Published: March 2010

Allometric scaling is useful in the preclinical drug development phase to project pharmacokinetic parameter values determined experimentally in a few animal species to other species and ultimately to humans. Such projection permits early decisions about the developmental prospects for candidate drugs and forms a basis for selection of drug dosage to provide a desired level of systemic exposure. This article focuses on allometric scaling techniques in the context of the preclinical drug development process.
Bioavailability and Bioequivalence Studies
Authors: Lyubimov Alexander V. , Bekersky Ihor
Published: March 2010

Toxicology/safety studies in animals are an integral part of any drug development program, the results of which have a direct impact on both the IND and the NDA. Both bioavailability and bioequivalence concepts are applied to animal toxicology studies to determine and confirm the exposure needs in order to calculate the animal to human safety margins. This article focuses on bioavailability/bioequivalence (BA/BE) studies, IND‐targeted nonclinical development, and NDA‐targeted nonclinical development.
Mass Balance Studies
Authors: Beumer Jan H. , Eiseman Julie L. , Egorin Merrill J.
Published: March 2010

A well‐designed mass balance study significantly expands information about the pharmacological behavior of an active compound. A preclinical mass balance study can elucidate excretory pathways, organ distribution of parent drug and metabolites, and metabolic profiles. This article focuses on the design, methodologies, and expertise required for the conduct of preclinical mass balance studies.
Physiologically Based Pharmacokinetic Modeling
Authors: Clewell Harvey J. , Reddy Micaela B. , Lave Thierry , Andersen Melvin E.
Published: March 2010

In the pharmaceutical area, the use of physiologically based pharmacokinetic (PBPK) models was limited in drug development due to the perceived mathematical complexity of the models and the labor‐intensive input data required. However, advances in the prediction of hepatic metabolism and tissue distribution fromin vitroandin silicodata have made the use of these models more attractive, providing the opportunity to gain mechanistic insight into the compound's properties. This article provides information necessary to understanding the application of PBPK models in preclinical drug development and advances in the available tools.
Mathematical Modeling as a New Approach for Improving the Efficacy/Toxicity Profile of Drugs: The Thrombocytopenia Case Study
Authors: Agur Zvia , Elishmereni Moran , Kogan Yuri , Kheifetz Yuri , Ziv Irit , Shoham Meir , Vainstein Vladimir
Published: March 2010

Biomathematics has enabled the development of a range of new theories dealing with significant problems of disease progression and control, hitherto beyond the reach of “snapshot”, experimental biology. Mathematical modeling of the underlying pathological and physiological processes in a patient is tied with the detailed relevant pharmacokinetics (PK) and pharmacodynamics (PD) that provides improved understanding of how the aspects of treatment scheduling may affect the patient. This article discusses the application of mathematical modeling tools to elucidate the hematological disorder thrombocytopenia in different animal species, and to accurately describe the efficacy and safety of the thrombocytopenia‐alleviating drugs, thrombopoietin, and interleukin‐11.
Data Analysis
Authors: Vora Jayesh , Desai Pankaj B.
Published: March 2010

Pharmacokinetic analysis of systemic (or blood or plasma) concentration‐time data, or amount excreted in urine over various time intervals, represents a critical activity in the preclinical development of drug candidates. Noncompartmental or compartmental methods, based on statistical moment theory, are generally employed to perform these analyses. This article discusses noncompartmental methods of pharmacokinetic analysis with primary emphasis on data analysis following intravenous and oral dosing.
Relationship between Animal Models and Clinical Research: Using Mucositis As A Practical Example
Authors: Gibson Rachel J. , Bowen Joanne M. , Keefe Dorothy M. K.
Published: March 2010

Mucositis is a major clinical problem in oncology, caused by the cytotoxic effects of cancer chemotherapy and radiotherapy. The strong relationship between animal investigation and translation to the clinical setting has provided medical research fraternity with an opportunity to conduct effective research in the field of oncology. This article describes the use of animal models for research of the clinical problem of mucositis.
Bacterial Mutation Assay
Authors: Kumpati Premkumar
Published: March 2010

The bacterial mutation assay is a reliable and extensively used short‐term assay for initial screening of chemicals/drugs for their potential mutagenic/carcinogenic activity. But short‐term tests have their own advantages and limitations. This article presents an overview of the utilization of bacterial systems for mutagenic and carcinogenic chemicals.
Immunotoxicity Testing:ICHGuidelineS8 and Related Aspects
Authors: Pauels Hans‐Gerd , Taylor John
Published: March 2010

Immunotoxicology has evolved as a discipline concerned with adverse interactions of chemicals and drugs with the immune system. Immunotoxicologists have long focused on immunosuppression, but other aspects of immunotoxicity like immunogenicity, induction of autoimmunity, or hypersensitivity have become increasingly important for drugs. This article presents an overview of regulatory ICH Guideline S8 and other regulatory provisions related to immunotoxicity testing.
Reproductive and Developmental Toxicology
Authors: Hood Ronald D. , Parker Robert M.
Published: March 2010

The design and conduct of developmental and reproductive toxicity (DART) studies and juvenile animal studies for pediatric drugs are among the most difficult in toxicology. DART studies require highly trained and skilled technicians to properly evaluate the reproductive and developmental aspects. The article addresses testing protocols for reproductive and developmental toxicology.
In Vitro
Toxicokinetics and Dynamics: Modeling and Interpretation of Toxicity Data
Authors: Bruinink Arie
Published: March 2010

Knowledge about toxicokinetics and toxicodynamics is of crucial importance for various areas of pharmaceutical research. Toxicokinetics is generally regarded as an area of science that deals with kinetics of exposure, absorption, distribution, metabolism, and excretion of test compounds and metabolites. This article describes
in vitro
concentration‐effect relationships and also discusses tools to elucidate the toxicomechanisms under
in vitro
conditions.
Secondary Pharmacodynamic Studies andIn vitroPharmacological Profiling
Authors: Armstrong Duncan , Migeon Jacques , Rolf Michael G. , Bowes Joanne , Crawford Mark , Valentin Jean‐Pierre
Published: March 2010

Pharmacological investigations during the drug discovery and development process are broadly divided into three distinct categories: primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacological studies. Secondary pharmacodynamic studies form an important aspect of pharmacological investigations during the drug discovery process. This article discusses drivers for secondary pharmacodynamic studies, different strategic approaches to such studies, and the impact of pharmacological profiling on the drug discovery process.
Proteomics
Authors: Casado Juan , Casal J. Ignacio
Published: March 2010

Proteomics is a branch of study dedicated to the biological implication of proteins in disease, pathologies, or alterations of living organisms. One of the most important steps in a proteomic study is the selection of the biological material to work with. The article describes various methods and steps in a proteomic study, including electrospray ionization of proteins and multidimensional liquid chromatography.
Toxicogenomics in Preclinical Development
Authors: Blomme Eric A. G. , Semizarov Dimitri , Waring Jeffrey F.
Published: March 2010

Toxicogenomics refers to a technology wherein gene expression analysis is used in the field of toxicology. Toxicogenomics is based on the relatively simple assumption that toxicants acting through a similar mechanism of action will generate similar gene expression profiles. This article discusses the importance of toxicogenomics in drug discovery and mechanistic toxicology.
Regulatory Considerations
Authors: Siegel Evan B. , Lakings Duane B.
Published: March 2010

The rapidly increasing cost of new drug development has led to unprecedented pressures on sponsors to concentrate largely on human clinical trials. The ICH S7a guideline recommends that a standard set of safety pharmacology (SP) studies be conducted prior to the initiation of preclinical trials on a new drug substance. The article discusses preclinical drug development studies considered necessary to effectively characterize the pharmacology, pharmacokinetic, and toxicology profiles of drug candidates.
Regulatory Issues in Preclinical Safety Studies (
U
.
S
.
FDA
)
Authors: Hastings Kenneth L. , Brock William J.
Published: March 2010

It is of practical importance to understand the scientific approach that drives decision making in the drug review divisions that constitute the real world of pharmaceutical development. An issue that often arises in the nonclinical toxicology evaluation of drugs is the role of acute dose studies. The article discusses regulatory issues and guidelines in preclinical safety studies set by the U.S. Food & Drug Administration (FDA).
Selection and Utilization of
CROs
for Safety Assessment
Authors: Kopplin Joanne R. , Richter Ward R.
Published: March 2010

Outsourcing preclinical development and drug safety testing to Contract Research Organizations (CROs) has become very common in the biopharmaceutical, chemical, medical device, and food additive industries. Contract Research Organizations (CROs) conducting preclinical testing provide services in pharmacology, pharmacokinetics, analytical chemistry, toxicology, pathology, and associated disciplines. This article discusses processes for working with preclinical CROs.
Drug Impurities and Degradants and Their Safety Qualification
Authors: Guy Robin C.
Published: March 2010

Impurities in drug products have triggered numerous laws and amendments in the U.S. Through the years, the U.S. Food and Drug Administration (FDA) and other international regulatory agencies have set regulations and guidelines for the handling of impurities in pharmaceuticals. This article discusses various aspects of drug impurities and their safety qualifications.
Bridging Studies in Preclinical Pharmaceutical Safety Assessment
Authors: Gad Shayne Cox
Published: March 2010

Preclinical toxicology bridging studies are unique to the safety evaluation of pharmaceuticals. Simple parallel comparative toxicity studies are commonly performed to establish that the active pharmaceutical ingredient (API) and/or clinical product are pharmacokinetically and toxicologically equivalent. This article discusses various aspects of preclinical pharmaceutical safety assessment in drug development studies.
Historical Perspective
Authors: King Roberta S.
Published: March 2010

Issues that have been debated throughout the history of drug metabolism are still disputed to some degree. Physiological function of drug metabolism has broadened to include endogenous compounds and endogenous regulatory pathways. The article offers insights into the history of drug metabolism studies, with special emphasis on enzymatic metabolism of drugs.
In VivoMetabolite Kinetics
Authors: Yang Zheng
Published: March 2010

Information on active metabolites and their kinetics in the body is essential to comprehending the pharmacokinetic pharmacodynamic relationships of drugs. With recent advancement in bioanalytical techniques, many of pharmacologically active metabolites can be identified at the early stages of drug discovery. Knowledge of how metabolites distribute and accumulate in tissues is valuable to biotransformation‐based toxicity. This article discusses the concepts and principles ofin vivodrug metabolite kinetics.
Mass Spectrometry
Authors: Sharp Thomas R.
Published: March 2010

Mass spectrometry has become one of the most acceptable methods for determining organic structure, and is generally the first line of experimentation done for determining the structure of organic molecules. Mass spectrometry, coupled with liquid chromatography, acts as a foundation experimental technique in drug metabolism. This article discusses the importance of mass spectrometry in drug research.
Minimizing the Potential for Drug Bioactivation of Drug Candidates to Success in Clinical Development
Authors: Nassar Ala F.
Published: March 2010

Variations in human drug‐metabolizing enzymes can produce subtle evidence of potential toxicity. There are indications that some substructures found in drugs can form reactive metabolites that are involved in toxicities in humans. This article discusses the recent efforts to overcome and assess the problem of reactive metabolites in drug discovery and development, which might help to evaluate the safety profile of new drug candidates for idiosyncratic drug reactions (IDRs) during the preclinical phase.
Screening for Reactive Metabolites Using Genotoxicity Arrays and Enzyme/DNABiocolloids
Authors: Rusling James F. , Hvastkovs Eli G. , Schenkman John B.
Published: March 2010

High percentage of drug development failures are linked to toxicity issues, and unfortunately some of these do not come to light until clinical trials or even after the drug is introduced to the market. A wide variety of strategies have been proposed for early toxicity prediction, includingin silicomethods along with a range ofin vitroandin vivobiological approaches. This article describes new array‐based methodology utilizing enzyme/DNA films to screen for reactive drug metabolites based on a DNA‐damage end point measured by electrochemiluminescence (ECL).
Characterization of CytochromeP450 Mechanism‐Based Inhibition
Authors: Rock Dan , Wienkers Larry C.
Published: March 2010

Oxidative metabolism mediated by the group of hepatic enzymes known as the cytochrome P450 represents a significant clearance pathway for many drugs prescribed today. Given the poor predictability of preclinical in vivo models for toxicity, in vitro systems continue to provide important experimental support for safe therapeutics. This article discusses various aspects of characterization of cytochrome P450 mechanism‐based inhibition.
The Role of Drug Metabolism in Toxicity
Authors: Davis Carl D. , Hanumegowda Umesh M.
Published: March 2010

Drug toxicity and the factors that govern it are quite complex. In drug discovery, toxicity can depend on factors that may be species‐specific, thus forcing toxicologists to determine the relevance of toxicity in animals to that in humans. The article presents some key characteristics of the common enzymes encountered in metabolic clearance of drugs.
Allergic Reactions to Drugs
Authors: Grillo Mark P.
Published: March 2010

Allergic reactions to drugs can lead to potentially life threatening reactions such as asthma, anaphylaxis, dermatitis, hepatitis, hemolytic anemia, lupus, and nephritis. An increased understanding of how and why allergic reactions to drugs occur should assist in improving decision‐making processes for the selection of safer drug candidates. This article discusses some of the proposed chemical mechanisms by which drugs cause allergic reactions.
An Introduction to Toxicogenomics
Authors: Vollrath Aaron L. , Bradfield Christopher A.
Published: March 2010

The methodological domain of toxicogenomics is quite broad and growing rapidly. The growth of toxicogenomics is largely due to the complete sequencing of a growing number of genomes, coupled with the development of novel technologies that allow medical fraternity to detect chemically induced changes in global gene transcription. The article focuses on the application of microarray gene expression in the context of toxicogenomics.
Biopharmaceuticals: Definition and Regulation
Authors: Tsang Lincoln , Cortez Nathan
Published: March 2010

Compared with conventional small‐molecule drugs, products derived from a biological source are structurally complex and involve manufacturing processes that require tight control to ensure their safety, quality, and efficacy. Because of these differences in respect of the product characteristics and manufacturing process, the regulatory supervision of biological products is distinguishable from conventional pharmaceutical products based on small molecules. This article addresses legal framework governing biological products in Japan, the United States, and the European Union.
Methods of Production of Biopharmaceutical Products and Assessment of Environmental Impact
Authors: Williams Patricia D.
Published: March 2010

Advances in molecular biology and genetics have played significant roles in the development of biopharmaceutical products. Novel approaches such as host system, protein purification, and characterization techniques have been developed to increase the capacity, efficiency, and safety of biopharmaceuticals. This article focuses on systems available for production of biopharmaceuticals and the approaches to introducing new technologies into the drug development process.
The Principles of
ICH
S
6 and the Case‐by‐Case Approach
Authors: Cavagnaro Joy A.
Published: March 2010

The conduct of toxicology studies in laboratory animals has been driven by experience, historical precedence, and governmental requirements, and the results of these studies have led to restrictions on the use, or method of use, of the chemicals concerned. The ICH S6 guideline provides a framework for preclinical safety evaluation programs used for assessing toxicity of biopharmaceuticals. This article focuses on the ICH S6 Guidance and case‐by‐case approach for preclinical safety assessment of biopharmaceuticals.
Implementation of
ICH
S
6:
EU
Perspective
Authors: Ryle Peter R. , Snodin David J.
Published: March 2010

The EU approach to preclinical testing of biopharmaceutical products is firmly anchored around the principle laid out in the ICH S6 guideline. The approach from a technical and scientific viewpoint can be regarded as similar to that in the other major ICH regions (the United States and Japan). The major difference relates to the regulatory administrative structure within the European Union, such as interaction of sponsor with EU national authorities. This article focuses on the major differences in regulatory structure between the European Union and other regions, which has bearing on obtaining regulatory guidance and scientific advice during the development of a biopharmaceutical for the European market.
Implementation of
ICH
S
6: Japanese Perspective
Authors: Nakazawa Takahiro
Published: March 2010

The safety assessment of biopharmaceuticals in preclinical studies has been improved in Japan with the implementation of the ICH S6 and Points‐to‐Consider document. The analysis of data from a questionnaire survey conducted by JPMA suggests that the ICH S6 was well understood and adequately implemented in Japan. The Japanese Points‐to‐Consider document helps industry scientists and regulatory reviewers understand the ICH S6 guideline and case‐by‐case approaches to preclinical programs.
Implementation of
ICH
S
6:
US
Perspective
Authors: Cosenza Mary Ellen
Published: March 2010

In the United States, biopharmaceutical products have been developed in accordance with ICH S6 since its publication in 1997. The ICH S6 document creates a case‐by‐case, science‐driven approach to biotechnology preclinical product development, providing information and for designing and conducting clinical trials. This article reviews specific sections and considerations of the ICH S6 document and discuss how this guidance has been implemented in the United States.
Comparison of Preclinical Development Programs for Small Molecules (Drugs/Pharmaceuticals) and Large Molecules (Biologics/Biopharmaceuticals): Studies, Timing, Materials, and Costs
Authors: Horvath Christopher
Published: March 2010

Successful and efficient development of a new pharmaceutical requires the planning of an integrated development program that coordinates the trilogy of product manufacture—chemistry, manufacturing, and controls (CMC), preclinical studies (distribution, metabolism, and pharmacokinetic [DMPK], pharmacology and toxicology), and clinical trials—within the framework of the regulatory development strategy. Preclinical safety studies must support each successive phase of clinical development, as well as any significant changes to the method(s) of manufacturing, formulating, or administering the pharmaceutical. This article aims to compare the studies, materials, and costs associated with hypothetical preclinical development programs intended to support the clinical development of a small molecule (drug) and a large molecule (biologic).
Selection of Relevant Species
Authors: Subramanyam Meena , Rinaldi Nicola , Mertsching Elisabeth , Hutto David
Published: March 2010

It is important to select a relevant species for conducting safety assessment studies to mimic putative interpatient treatment differences in test article responsiveness and understand the rank order pharmacologic sensitivity of the relevant common laboratory animal species. Appropriate selection of a pharmacologically relevant species will also enable identification of factors that affect the therapeutic index of biopharmaceutical. This article discusses various experimental approaches used to select the relevant species for conduct of toxicology studies for biopharmaceuticals and advances made in scientific approaches to facilitate this process.
PhysiologicIgGBiodistribution, Transport, and Clearance: Implications for Monoclonal Antibody Products
Authors: Rojko Jennifer L. , Price‐Schiavi Shari
Published: March 2010

Following administration, monoclonal antibodies become part of the endogenous IgG pool for distribution, transport, and clearance unless these physiologic processes are altered by antibody CDR‐epitope interactions. This article aims to provide helpful information regarding potential monoclonal antibody IgG test article (non‐CDR‐mediated) binding to specific tissues, cell types or other tissue elements, and subcellular locations following exogenous intravenous administration in animal model test systems.
The Role of Pharmacokinetics and Pharmacodynamics in Selecting a Relevant Species
Authors: Green Martin D. , Hartsough Melanie
Published: March 2010

The appropriate selection and use of a relevant animal species in preclinical toxicity testing is dependent on pharmacokinetic (PK) and pharmacodynamic (PD) measures. These measures are fundamental for the extrapolation of the preclinical toxicity data to the clinical situation. The article provides information regarding the appropriate selection and use of a relevant animal species in preclinical toxicity testing.
Use of Animal Models of Disease in the Preclinical Safety Evaluation of Biopharmaceuticals
Authors: Te Koppele Johan , Witkamp Renger
Published: March 2010

Animal models for human disease are mostly used to evaluate preclinical safety of biopharmaceuticals. Safety evaluation includes: improving prediction of the toxicity or therapeutic index, supporting the mechanistic interpretation of safety studies, and evaluating the undesirable disease progression. This article focuses on general considerations regarding the use of animal models for disease.
Safety Pharmacology: Similarities and Differences between Small Molecules and Novel Biopharmaceuticals
Authors: Bernton Edward W.
Published: March 2010

Safety pharmacology studies of small molecule drugs are conducted to investigate unsuspected “off‐target” activities and adverse effects associated with the specific therapeutic class of the drug candidate or preclinical studies. The safety evaluation of new biopharmaceuticals is often made more difficult by the higher percentage of novel drug targets, compared to small molecules. For these products, safety pharmacology tends to be a more focused investigation of highly specific drug‐target interactions, and an in‐depth characterization of pharmacodynamic effects.
Genetic Toxicology Testing of Biopharmaceuticals
Authors: Jacobson‐Kram David , Ghantous Hanan
Published: March 2010

Genotoxic risks of pharmaceuticals are assessed by genetic toxicity assays. The assays rely on cytotoxicity to ensure assay validity. Performance of the assays is influenced by properties of the biopharmaceutical, synthesis techniques, product stability, presence of residual organic chemicals, and pharmacology. This article focuses on genetic toxicity testing of biopharmaceuticals.
General Toxicity Testing and Immunotoxicity Testing for Biopharmaceuticals
Authors: Bussiere Jeanine L.
Published: March 2010

Toxicity testing of biopharmaceuticals is highly dependent on species specificity. If the molecule is pharmacologically active in both rodent and nonrodent species, then the toxicology studies should be conducted in two species. On the other hand, alternative strategies for conducting safety studies such as testing with surrogate molecules, or using transgenic/knockout mice, need to be considered if the molecule is not active in nonhuman primates.
Reproductive/Developmental Toxicity Assessment of Biopharmaceuticals in Nonhuman Primates
Authors: Weinbauer Gerhard F. , Frings Werner , Fuchs Antje , Niehaus Michael , Osterburg Ingrid
Published: March 2010

Developmental and reproductive toxicity (DART) evaluation of biopharmaceuticals frequently necessitates the use of nonhuman primate models (NHPs) owing to species specificity. NHPs offer several advantages over rodents and rabbits with regard to DART because of similarity to human. This article provides a state‐of‐the‐art account on the feasibility and limitations of using NHPs for DART evaluation in the context of preclinical development of biopharmaceuticals.
Immunogenicity of Therapeutic Proteins and the Assessment of Risk
Authors: Schellekens Huub , Jiskoot Wim
Published: March 2010

Nearly all therapeutic proteins induce an immune response. The immunogenic response may lead to complications such as skin reactions, anaphylaxis‐like reaction, transfusion reactions, and serum sickness due to immunogenic response to impurities and contaminants. This article focuses on risk analysis and management program for new therapeutic proteins and the factors influencing the probability of an antibody response.
Current Practices in the Preclinical Safety Assessment of Peptides
Authors: Heidel Shawn M. , Page Todd J.
Published: March 2010

There has been an explosion of peptides in drug development and there are currently dozens of marketed therapeutic peptides. The road map for developing peptides is by association to existing biopharmaceutical and/or new chemical entity guidance documents rather than a guidance that is specific for peptides. This article reviews the preclinical development experience across therapeutic peptides, highlighting what has gone before and some considerations for the future.
Strategy Considerations for Developing the Preclinical Safety Testing Programs for Protein Scaffold Therapeutics
Authors: Roberts Stanley A. , Woodnutt Gary , Bradshaw Curt W.
Published: March 2010

This article focuses on key issues pertaining to the design of the preclinical safety assessment program for protein scaffold therapeutics. These new compounds are diverse and include several different protein scaffolds such as monoclonal antibodies, transferrin, and albumin. Small pharmacologically active molecules are attached to the scaffolds so that these therapeutics can have many potential modes of intended pharmacologic action.
Preclinical Safety Evaluation of Immunotoxins
Authors: Brown Jennifer G. , Entwistle Joycelyn , Glover Nick , Macdonald Glen C.
Published: March 2010

Immunotoxins continue to be actively investigated as viable alternatives to conventional therapies for a variety of diseases. An array of different recombinant, antibody formats have improved the overall in vitro and preclinical in vivo efficacy of immunotoxins. This article describes the development of immunotoxins and the preclinical development required for advancing VB4‐845, an anti–EpCAM targeting scFv linked to a truncated form of Pseudomonas exotoxin A(252‐608), into the clinic.
Preclinical Safety Evaluation of Viral Vaccines
Authors: Dempster A. Marguerite , Haworth Richard
Published: March 2010

For nearly a century vaccines have proved to be one of the most important and effective medical treatments. Vaccines continue to prevent millions of deaths worldwide and protect children from a variety of serious diseases such as diphtheria, pertussis, measles, tetanus, and rubella. This article focuses on the preclinical safety evaluation strategy for vaccine approaches to the prophylaxis and treatment of viral diseases.
Preclinical Safety Evaluation of Biopharmaceuticals
Authors: Serabian Mercedes A. , Huang Ying
Published: March 2010

Preclinical studies for any experimental pharmaceutical agent, including gene therapy products, are conducted to provide better scientific insight into the potential pharmacologic and toxiologic effects that may result from the administration of the agent in humans. These studies are critical for helping to define the risk‐benefit ratio of the experimental agent of interest in the desired clinical population prior to initiation of a clinical trial and throughout the development program for the pharmaceutical agent. This article provides a perspective of the preclinical assessment of gene therapy products intended for clinical use in therapeutic indications.
Tissue Engineered Products: Preclinical Development of Neo‐Organs
Authors: Bertram Timothy A. , Jayo Manuel
Published: March 2010

Tissue engineering draws on specialized expertise from two traditional disciplines: engineering and the life sciences. The combination of these disciplines forms a foundation upon which the commercial development of neo‐organs is possible. This article discusses development challenges and available solution strategies for bringing these transformational technologies to patients in need.
GLP
Requirements and Current Practices
Authors: Scharton‐Kersten Tanya
Published: March 2010

It is expected by the US FDA that all preclinical safety studies supporting the safety of research or marketing application will be performed in a manner consistent with GLP provisions and that sponsors justify any non‐conformance. Application of GLP principles to testing of biopharmaceuticals, including cell therapies and infectious agent vaccines and therapies, can be difficult. This article focuses on the U.S. and global GLP regulations.
Preclinical Assessment of Safety in Human Subjects
Authors: Wintering Nancy , Newberg Andrew B.
Published: March 2010

Preclinical safety studies of human subjects are an essential step in the drug development process. These studies provide valuable information for the investigational new drug (IND) application and the investigational drug brochure. This article focuses on the main issues related to preclinical studies of safety in human subjects.
Adaptive Research
Authors: Rosenberg Michael
Published: March 2010

Adaptive research denotes an approach to clinical trials that incorporates what is learned during the course of a study or development program into how it is completed, without compromising validity or integrity. The goal of adaptive research is to make better and accurate decisions to allocate all study resources more efficiently, reduce costs and timelines, and better achieve informational goals. This article describes different types of adaptive techniques.
Process of Data Management
Authors: Trocky Nina , Brandt Cynthia
Published: March 2010

The process of data management is composed of various discrete and interrelated activities that are linked in an individual and building in a successive fashion. The data management study plan (DMSP) can provide the framework for how and where the processes and procedures are defined and outlined for individual protocols or studies. This article discusses quality plan, data management team structure, case report form (CRF) design and guidelines, and data acquisition and handling guidelines.
Designing and Conducting PhaseIIIStudies
Authors: Saba Nabil , Kauh John , Shin Dong M.
Published: March 2010

Phase III studies are defined as randomized controlled studies enrolling large numbers of patients with the purpose of rendering a definitive assessment of how effective the studied intervention is, compared with the existing standard of care. The randomized clinical trial is characterized by two or more therapeutic treatment groups. This article focuses on design and conduct of phase III studies.
Regulatory Approval
Authors: Henry Fred , Shih Weichung J.
Published: March 2010

Clinical trial conduct is governed by national laws that are supplemented by international, regional, and national guidance documents. Fast‐track approval programs emphasize the critical nature of close, early communication between the FDA and sponsors. This article describes activities necessary to achieve and maintain regulatory clearance for the conduct of clinical trials and some general strategies for the cooperative design of clinical programs to support marketing approval.
New Paradigm for Analyzing Adverse Drug Events
Authors: Szarfman Ana , Levine Jonathan G. , Tonning Joseph M.
Published: March 2010

A new paradigm for computer‐assisted analysis of adverse drug events is sorely needed. Critics of the current paradigm emphasize the need for more transparency in the data review process, claiming that there is the potential for suppressing negative results or for hiding safety issues in both interventional and observational studies. It is essential to transition from quasi‐computerized methods, in which the different elements of the analytical process are treated as discrete, paper report tasks, to a comprehensive informatics approach, in which the entire data collection and analysis is considered as a single reusable, extensible, auditable, and reproducible system.
Gynecology Randomized Control Trials
Authors: Khan Khalid S. , Selman Tara , Daniels Jane
Published: March 2010

Randomized control trials (RCTs) are widely accepted as a gold standard for scientific evaluation of all treatments. Benign gynecological conditions such as chronic pelvic pain, heavy menstrual bleeding, and subfertility can be treated with suboptimal therapies when there is not a commitment to the development of new drugs and a thorough evaluation of the relative merits of existing ones. This article focuses on the issues regarding the design and analysis of RCTs that are pertinent to benign gynecology.
Pharmacological Treatment Options for Nonexudative and Exudative Age‐Related Macular Degeneration
Authors: Oliver Alejandro , Ciulla Thomas A. , Harris Alon
Published: March 2010

Age‐related macular degeneration (AMD) is the leading cause of vision loss in the developed world. Any patient who exhibits signs and symptoms consistent with exudative AMD undergoes a thorough dilated fundus exam, stereo color fundus photography, and rapid sequence fluorescein angiography (RSFA). The treatment options for ARM and nonexudative AMD are limited; therefore, prevention of disease progression is viewed as critical.
Bridging Studies in Pharmaceutical Safety Assessment
Authors: Ruckle Jon
Published: March 2010

With globalization making an impact on the pharmaceutical industry, there is an increasing urgency for international regulatory approval and marketing of pharmaceutical compounds in the globalization. Bridging studies are performed to facilitate approval of a medication in a new region after it has already been studied or approved in another region. This article discusses some important issues regarding bridging studies, such as dose selection, product labeling, safety, tolerability, and monitoring of the medication in a new region.
Methods of Randomization
Authors: McPherson Gladys , Campbell Marion
Published: March 2010

Randomization is increasingly being used to eliminate the problem of predictability and at the same time to maintain balance across combinations of factors in a clinical trial. The most important factors when choosing a randomization method are the size of the trial, practicality of the method, maintaining the blind, and reducing predictability. This article focuses on the different classes of randomization procedure and factors that influence the trials.
Biomarkers
Authors: Bleavins Michael R. , Carini Claudio , Jurima‐Romet Malle , Rahbari Ramin
Published: March 2010

Biomarkers are valuable tools for drug development that provide accurate information regarding drug performance and/or disease progression. Proper incorporation of biomarkers in drug development strategy enables the concept of “fail fast, fail early,” allowing early identification of the extremely high proportion of compounds that fail during drug development. This article discusses all the issues related to the use of biomarkers in diagnosis, prognosis, drug discovery and development.
Blinding and Placebo
Authors: Bauhofer Artur
Published: March 2010

Blinding refers to keeping persons, such as participants, investigators, and data assessors, unaware of the allocated treatment or therapy, so that they are not influenced psychologically or physically by that knowledge. Placebos are used to make patients’ and observers’ attitudes to the trial as similar as possible in treatment and control groups and to perform an efficient double‐blinded trial. This article describes important features of placebo and blinding trials for the assessment of outcomes with high expectation influence.
Pharmacology
Authors: Buclin Thierry
Published: March 2010

Pharmacology
, oriented toward characterization of drug properties in humans, plays an important role both in drug development and in optimization of patient care. Clinical
pharmacology
uses specific methodological approaches to derive useful conclusions from clinical measurements, obtained during drug administration trials designed for that purpose. This article describes the specific methodological characteristics of clinical pharmacology trials.
Modeling and Simulation in Clinical Drug Development
Authors: Nedelman Jerry , Bretz Frank , Fisch Roland , Georgieva Anna , Hsu Chyi‐Hung , Kahn Joseph , Kawai Ryosei , Lowe Phil , Maca Jeff , Pinheiro José , Rossini Anthony , Schmidli Heinz , Steimer Jean‐Louis , Yu Jing
Published: March 2010

This chapter describes modeling and simulation (M&S) applied to clinical drug development within a pharmaceutical company. M&S is a tool that shows us how a drug works and helps us design and interpret clinical trials. M&S also serves as a framework for what we learn in the precise language of mathematics.
Inference Following Sequential Clinical Trials
Authors: Liu Aiyi , Yu Kai F.
Published: March 2010

Group sequential testing procedures are increasingly being used to monitor
clinical trials, especially phase III studies comparing the efficacy of two or more treatment agents. In a group sequential clinical trial a set of stopping boundaries are usually specified for a test statistic at a few time points, either in terms of real calendar time or statistical information. This article focuses on several popular approaches to construct point and interval estimation and
P
values with respect to the primary endpoint following the termination of a sequential phase III trial and methods for inference concerning a secondary endpoint.
Statistical Methods for Analysis of Clinical Trials
Authors: Wang Duolao , Bakhai Ameet , Maffulli Nicola
Published: March 2010

Randomized controlled trials are regarded as the most robust form of evidence based medicine. An appreciation of statistical methods is fundamental to understanding randomized trial methods and results. This article focuses on statistical approaches to dealing with data and samples of clinical trials.
Proof‐of‐Principle/Proof‐of‐Concept Trials in Drug Development
Authors: Al‐Shurbaji Ayman
Published: March 2010

The importance of early Proof‐of‐Principle/Proof‐of‐Concept (PoP/PoC) trial becomes apparent in the context of high attrition rate in drug development. A positive PoP/PoC significantly improves the chance of finding a partner or successfully licensing out the compound. This article focuses on the biomarkers, pharmacogenomics, proteomics, metabonomics, medical imaging, pharmacological models, and nonpharmacological models in PoP/PoC trials.