bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug Clearance
Authors: Panuganti Sree D. , Svensson Craig K. 
Published: March 2010

AbstractThe 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

AbstractThe 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

AbstractMetabolite 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

AbstractAllometric 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

AbstractToxicology/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

AbstractA 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

AbstractIn 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

AbstractBiomathematics 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

Abstract
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

AbstractMucositis 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.
Immunotoxicity Testing:ICHGuidelineS8 and Related Aspects
Authors: Pauels Hans‐Gerd , Taylor John 
Published: March 2010

AbstractImmunotoxicology 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.
In Vitro
Toxicokinetics and Dynamics: Modeling and Interpretation of Toxicity Data
Authors: Bruinink Arie 
Published: March 2010

Abstract

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

AbstractPharmacological 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

Abstract
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

AbstractToxicogenomics 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.
In VivoMetabolite Kinetics
Authors: Yang Zheng 
Published: March 2010

AbstractInformation 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.
Minimizing the Potential for Drug Bioactivation of Drug Candidates to Success in Clinical Development
Authors: Nassar Ala F. 
Published: March 2010

AbstractVariations 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

AbstractHigh 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

AbstractOxidative 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

AbstractDrug 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

AbstractAllergic 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

AbstractThe 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

AbstractFollowing 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

AbstractThe 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

AbstractAnimal 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.