Drug Discovery And Evaluation Methods In Clinical Pharmacology

Drug Discovery and Evaluation has become a more and more difficult, expensive and time-consuming process. The effect of a new compound has to be detected by in vitro and in vivo methods of pharmacology. The activity spectrum and the potency compared to existing drugs have to be determined. As these processes can be divided up stepwise we have designed a book series "Drug Discovery and Evaluation" in the form of a recommendation document. The methods to detect drug targets are described in the first volume of this series "Pharmacological Assays" comprising classical methods as well as new technologies. Before going to man, the most suitable compound has to be selected by pharmacokinetic studies and experiments in toxicology. These preclinical methods are described in the second volume „Safety and Pharmacokinetic Assays". Only then are first studies in human beings allowed. Special rules are established for Phase I studies. Clinical pharmacokinetics are performed in parallel with human studies on tolerability and therapeutic effects. Special studies according to various populations and different therapeutic indications are necessary. These items are covered in the third volume: „Methods in Clinical Pharmacology".

This is the second edition of a well-received book in the series “Drug Discovery and Evaluation” The completely revised new edition of the volume reflects the current state of the art in Clinical Pharmacology. Drug Discovery and Evaluation has become a more and more difficult, expensive and time-consuming process. The effect of a new compound has to be detected by in vitro and in vivo methods of pharmacology. The activity spectrum and the potency compared to existing drugs have to be determined. As these processes can be divided up stepwise we have designed a book series "Drug Discovery and Evaluation" in the form of a recommendation document. Clinical pharmacokinetics are performed in parallel with human studies on tolerability and therapeutic effects. Special studies according to various populations and different therapeutic indications are necessary. These items are covered in the third volume: „Methods in Clinical Pharmacology". For the 2nd edition of this volume, the chapters have been revised and completely updated. A large number of assays were added. New chapters were included, such as pain, addiction, gene therapy, orphan diseases.

The new edition of this successful reference offers both cutting-edge and classic pharmacological methods. Thoroughly revised and expanded to two volumes, it offers an updated selection of the most frequently used assays for reliably detecting the pharmacological effects of potential drugs. Every chapter has been updated, and numerous assays have been added. Each of the more than 1,000 assays comprises a detailed protocol outlining purpose and rationale, and a critical assessment of the results and their pharmacological and clinical relevance.

Many aspects of drug safety have become an outstanding and even persistent issue and may occur during the process of both drug discovery and development. Until 15 years ago, drug discovery and evaluation was primarily a sequential process starting with the selection of the most pharmacologically active compound from a series of newly synthesized small molecule chemical series by means of distinctive pharmacological assays. Safety aspects were addressed by evaluation of the selected compound at high doses in a series of specific studies directed at indications other than the intended indication of the new compound. These tests are then followed by pharmacokinetic studies, which are primarily conducted to confirm whether the selected compound possesses a suitable half-life for sufficient exposure and efficacy and, whether it has the desired properties specificity to the intended route of administration. Safety aspects relied predominantly on the conduct of single and repeat toxicologydose studies, which inform changes in organ structure rather than organ function. Both toxicological and pharmacokinetic studies are adapted to the progress of studies in clinical pharmacology and clinical trials. The new edition of this well and broadly accepted reference work contains several innovative and distinguished chapters. This "sequential" strategy has been abandoned with this new version of the book for several reasons: - Of the possible multitude of negative effects that novel drugs may impart on organ function, e.g. ventricular tachy-arrhythmia, many are detected too late in non-clinical studies to inform clinicians. On the other hand, negative findings in chronic toxicity studies in animals may turn out to be irrelevant for human beings. - New scientific approaches, e.g. high-throughput screening, human pluripotent stem cells, transgenic animals, knock-out animals, in silico models, pharmaco-genomics and pharmaco-proteomics, as well as Artificial Intelligence (AI) methods offered new possibilities. - There are several examples, that show that the "druggability" of compounds was considerably underestimated when the probability of success of a new project was assessed. The success rate in the pharmaceutical industry and the introduction of new chemical entities to the market per year dropped dramatically, whereas the development time for a new compound increased, sometimes exceeding the patent protection. Research and development scientists, involving the following changes, therefore adopted a change of strategy: - Parallel instead of sequential involvement of the various disciplines (multidimensional compound optimization). - The term "Safety Pharmacology" was coined. The International Conference on Harmonization (ICH) founded a Safety Pharmacology Working Group and the Safety Pharmacology Society (SPS) was launched. The discipline provided for evaluation, development and validation of a multitude of safety tests outlined in the 'Core Battery of Studies'. - Characterizing the exposure profile of a drug by conducting pharmacokinetic studies that evaluates the absorption, distribution, metabolism and excretion should to be investigated at an early stage of development as results contribute to the selection of a compound for further development. Advancements in Toxicology were achieved by the introduction of new methods, e.g., in silico methods, genetic toxicology, computational toxicology and AI. The book is a landmark in the continuously changing world of drug research and developments. As such, it is essential reading for many groups: not only for all students of pharmacology and toxicology but also for industry scientists and physicians, especially those involved in clinical trials of drugs, and for pharmacists who must know the safety requirements of drugs. The book is essential for scientists and managers in the pharmaceutical industry who are involved in drug discovery, drug development and decision making in the development process. In particular, the book will be of use to government institutions and committees working on official guidelines for drug evaluation worldwide.

The 4th edition of this successful reference book contains an updated selection of the most frequently used assays for reliably detecting the pharmacological effects of potential drugs. Effects covered include cardiovascular, analgesic, endocrine, psychotropic, respiratory, renal and immunomodulatory activities. Each of the more than 1,000 assays comprises a detailed protocol outlining the purpose and rationale of the method, a critical assessment of the results and their pharmacological and clinical relevance. In addition, animal models of rare diseases are described. For this 4th edition, all existing chapters have been revised and completely updated. A large number of assays were added. Sections that have been specifically enlarged include - Pharmacological assays in thrombosis and haemostasis, - Antidiabetic activity (includes completely new chapters such as Biochemical Methods in Diabetology), - Anti-atherosclerotic activity. New chapters are added such as Auditory Pharmacology, Oncology Activity, Stem Cells, Omics, Personalized Medicine, etc.

-A landmark in the continuously changing world of drugs -Essential reading for scientists and managers in the pharmaceutical industry involved in drug finding, drug development and decision making in the development process -Of use for government institutions and committees working on official guidelines for drug evaluation worldwide

Comprehensive reference on 700 of the most frequently used assays for reliably detecting pharmacological effects of potential drugs. For practitioners and students. Includes a full-text CD-ROM.

Maintaining a practical perspective, Bioequivalence and Statistics in Clinical Pharmacology, Second Edition explores statistics used in day-to-day clinical pharmacology work. The book is a starting point for those involved in such research and covers the methods needed to design, analyze, and interpret bioequivalence trials; explores when, how, and why these studies are performed as part of drug development; and demonstrates the methods using real world examples. Drawing on knowledge gained directly from working in the pharmaceutical industry, the authors set the stage by describing the general role of statistics. Once the foundation of clinical pharmacology drug development, regulatory applications, and the design and analysis of bioequivalence trials are established, including recent regulatory changes in design and analysis and in particular sample-size adaptation, they move on to related topics in clinical pharmacology involving the use of cross-over designs. These include, but are not limited to, safety studies in Phase I, dose-response trials, drug interaction trials, food-effect and combination trials, QTc and other pharmacodynamic equivalence trials, proof-of-concept trials, dose-proportionality trials, and vaccines trials. This second edition addresses several recent developments in the field, including new chapters on adaptive bioequivalence studies, scaled average bioequivalence testing, and vaccine trials. Purposefully designed to be instantly applicable, Bioequivalence and Statistics in Clinical Pharmacology, Second Edition provides examples of SAS and R code so that the analyses described can be immediately implemented. The authors have made extensive use of the proc mixed procedures available in SAS.