Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

Safety aspects have become an outstanding issue in the process of drug discovery and development. Until 15 years ago safety aspects were addressed by pharmacological testing of the selected compound in high doses in tests directed at indications other than the intended indication of the new compound. These tests were followed by pharmacokinetic studies, which were mainly aimed at confirming of a suitable half-life time and at oral activity. Safety aspects relied mostly on toxicity studies, which however gave information on changes of organ structure rather than on organ function. Toxicological and pharmacokinetic studies were adapted to the progress of studies in clinical pharmacology and clinical trails. But 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. A change of strategy was therefore adopted, involving the following changes:

-          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. Easily accessible and the most informative tests now have to be selected.

-          Exposure of a drug to the body by pharmacokinetic studies on absorption, distribution, metabolism and excretion has to be investigated at an early stage of development and can contribute to the selection of a compound for development.

Toxicology experienced major achievements by the introduction of new methods, e.g., in silico methods, toxicogenomics and toxicoproteomics.

The book is a landmark in the continuously changing world of drugs. As such it is important reading for many groups: not only for all students of pharmacology and toxicology but also for physicians, especially those involved in clinical trials of drugs, and for pharmacists who have to know the safety requirements of drugs.

The book is absolutely essential for scientists and managers in the pharmaceutical industry who are involved in drug finding, drug development and decision making in the development process.

In particular, the book will be of use for government institutions and committees working on official guidelines for drug evaluation worldwide.

H. Gerhard Vogel studied Pharmacy and Medicine at the Universities Erlangen and Tübingen (Germany). He received his Licensure as a Pharmacist in 1952 and as a Physician in 1956. His Doctorate in Medicine was gained in 1955. In 1963 he was designated a Fachpharmakologe DPhG. In 1967 he became Associate Professor in Pharmacology and Toxicology of the Department of Medicine, University of Marburg. In 1970 he was acknowledged as a Specialist for Pharmacology (Arzt für Pharmakologie). From 1972 he  taught students of Medicine, Pharmacy and Biology as an Honorary Professor in Pharmacology and Toxicology of the Faculty of Medicine, University of Marburg and from 1979 as an Honorary Professor in Pharmacology and Toxicology of the Faculty of Medicine, University of Frankfurt. After working as a resident in medicine in a city hospital, he joined the Department of Pharmacology of Farbwerke Hoechst AG, Frankfurt as a pharmacologist and endocrinologist in 1958. In 1969 he was made Director of the Department of Pharmacology at Hoechst, in 1977 Head of Pharma Research Experimental Medicine, in 1980 Head of Pharma Research, Preclinical Evaluation and Development, and in 1989 Head of the Decision Board on Pharmaceutical Development.

His scientific work was devoted to elaboration of new pharmacological methods, pharmacology of plant extracts from various countries, pharmacology of steroid hormones, pharmacology of peptide hormones, pharmacology of cardiac glycosides, biomechanics and biochemistry of connective tissue, experimental gerontology, experimental dermatology, development procedures for pharmaceutical products. He published more than 160 papers, mainly on new pharmacological methods, endocrinology, especially peptide endocrinology, biomechanics and biochemistry of connective tissue, such as skin and bone, and on other topics. He was a member of many international and national scientific societies, such as The New York Academy of Science,American Association for the Advancement of Science, German Society of Experimental and Clinical Pharmacology and Toxicology, International Society for Bioengineering and the Skin, European Association for the Study of Diabetes, German Society of Endocrinology, German Society of Diabetology, German Society Connective Tissue Research, German–Chinese Society of Medicine. He was a co-editor and contributor to several scientific textbooks. In 1997 he published together with Wolfgang H. Vogel the book Drug Discovery and Evaluation. Pharmacological Assays (Springer-Verlag), which appeared in a second completely revised, updated and enlarged edition with many contributions by his colleagues in 2002. A third edition was published in 2008.

Editorial Board:

Franz Jakob Hock received his Ph.D. degree (Sc.D.) in Zoology at the Institute of Neuroethology and Biocybernetics at the University of Kassel, Germany. He joined the Department of Pharmacology of the pharmaceuticalcompany Hoechst AG in 1976. He initially worked on methods in general pharmacology and nephrology, before becoming head of a laboratory devoted to pharmacological methods for drugs influencing memory and learning. He was then appointed Head of the Laboratory of General and Safety Pharmacology at the Frankfurt site of Aventis Pharma Deutschland GmbH. He received the degree of Fachpharmakologe DGPT (“certified expert pharmacology”) in 1981. In 1983 he spent a sabbatical year at the University of California, Irvine, at the Center for the Neurobiology of Learning and Memory (Director Prof. Dr. James L. McGaugh). He lectured for several years to students in Biology at the University of Kassel and the Technical University Darmstadt. He has published over 100 original papers on methods in Pharmacology and on new compounds. He is currently a member of the Task Force General/Safety Pharmacology German/Swiss Pharmaceutical Companies. He served several times as a member of the program committee ofthe Safety Pharmacology Society. He is a member of several domestic and international scientific societies. He now works as a consultant in pharmaceutical business development.

Jochen Maas is head of the Research and Development organization of the Diabetes Division within Sanofi and simultaneously General Manager Research & Development Germany. Previously he was head of the Drug Metabolism and Pharmacokinetics departments of Aventis in Frankfurt and in Paris. Educated at the universities of Heidelberg, Munich and Zurich, his  background includes degrees in Biology and Veterinarian Medicine. During his studies and researching for his thesis at the “Gesellschaft für Strahlen- und Umweltforschung“ in Munich-Neuherberg he collected his first experiences in Pharmacokinetics and in working with radiolabeled compounds. After a short period as assistant veterinarian in an animal hospital he joined the former Hoechst AG as Laboratory Head in 1992, performing various kinds of animal studies with radiolabeled isotopes in the life-science area of pharmaceutics, veterinarian medicine and crop science. During this time he completed his education as a specialist for Radiology. Following the break-up of the different parts of the company he became Section Head, responsible not only for carrying out but also for the analysis, evaluation and assessment of all kinds of pharmacokinetic and toxicokinetic animal studies. He took over the responsibility for the complete Drug Metabolism and Pharmacokinetics Department in Frankfurt in 2000. His activities ranged from in-silico approaches at very early stages of the value chain, in-vitro studies, and in vivo animal studies up to Phase I, II and III clinical studies. The whole scope of these activities from early research to late development is included in the pharmacokinetic part of this book. In 2003 he was appointed Head of Drug Metabolism and Pharmacokinetics in Paris working simulataneously in France and Germany. The mainobjective of his work was an intensive knowledge transfer from early parts of the value chain (“Research”) to the late stages (“Development”) and vice versa across the different disciplines. Today, one of his major interests is to bring together pharmacodynamic and pharmacokinetic research activities and to combine the obtained knowledge with safety aspects resulting in lower attrition rates at the later stage of the development.

Dieter Mayer studied veterinary medicine at the University of Munich, Germany. Thereafter, he worked on a thesis on biochemical mechanisms of heavy metal intoxication at the Institute of Pharmacology and Toxicology at the Ludwigs-Maximilian-University of Munich. In 1975 he joined Hoechst AG Frankfurt, Germany. He worked there at the Institute of Industrial Toxicology and was in charge of the safety assessment of Acesulfam, an artificial sweetener. Further projects consisted of fluorocarbons as replacements for chlorofluorocarbons. He contributedto the development of several pesticides.Dieter Mayer was a member of the German MAK (TLV) committee for about 12 years. He worked at the University of Davis, California and at the Centre International de Toxicologie (affiliation of Hoechst AG), Evreux, France, where he held the position of Scientific Director. In 1986 he became Head of the central toxicology department at Hoechst AG. This entailed responsibility for the entire Hoechst portfolio, and hence also for pharmaceuticals. He was involved in the successful development of anti-infectives, cardiovascular drugs, several insulins, CNS drugs and anti-rheumatics. In 1998 he was promoted to Vice President of Lead Optimization (Toxicology, DMPK and clin. Pharmacology).Prof. Mayer has been teaching toxicology at the University of Frankfurt since 1991 and has authored more than 90 scientific articles, abstracts and oral presentations. Today Dieter Mayer is a Consultant for the global pharmaceutical industry and is a member of the Advisory Board of National German Research Associations.