Abstract
A Comprehensive Guide to Toxicology in Preclinical Drug Development is a compilation of the long, complex, and very expensive processes that are encompassed under the rubric of drug development. Drug development presents an amalgam of diverse functions including drug discovery and synthesis, pre- and nonclinical development such as a drug’s characteristic adsorption, distribution, metabolism and excretion patterns (ADMEs), chemical and biological testing, pharmacokinetics, predictive toxicology, classic toxicology, genetics, toxicogenomics, safety pharmacology, clinical development, regulatory toxicology, and marketing and post-marketing development. Drug discovery is the initial process in drug development involving research leading to the identification of targets, their prioritization, and validation, resulting in lead compound optimization. The thrust of discovery involves the isolation of certain chemicals that interact with the target organ and have activities that would be beneficial in treating a specific disease. Even after a drug candidate is identified as a disease target and survives the rigors of the initial efficacy testing, most fail to progress along the drug development pathway because of safety issues identified during preclinical research process. The process is lengthy taking some 8+ years to bring a new drug entity to a point where it is approved for clinical use.
Given the scope of the investment, a biotech company must make to bring a new drug to market, novel predictive approaches to evaluating toxicity, and disease risk that have been recently developed and many are reviewed in this book. As one can imagine, trying to clearly describe to readers the many facets of such an intricate process in one place is a most ambitious undertaking. The book editor Dr Ali S. Faqi has assembled some 79 of the world’s experts and academicians in these various fields of endeavor to take on the challenge and hits it head on. The book is divided into 36 chapters covering many of the above-mentioned areas in considerable detail along with case study examples and in-depth discussions. Various technical topics include ADME, toxicokinetics where toxic in vivo doses are profiled, and pharmacokinetics where these toxic in vivo concentrations are compared and contrasted to the pharmacologically active doses. There is a chapter devoted to formulation development and the many variables necessary in setting dose levels, volumes, routes, and product solubility. There are also in-depth reviews of classical toxicological studies as they apply to preclinical studies in regulatory and safety evaluations and safety pharmacology covering objective, critical, and investigative analyses of all aspects of determining a safe clinical dose for clinical studies. Other technical chapters included topics such as genetic toxicology, clinical pathology, toxicological and molecular pathology, developmental and reproductive toxicology, immunotoxicology, juvenile toxicology, phototoxicity, carcinogenicity evaluations in 2-year rodent studies and in genetically engineered mice, monoclonal antibodies, ocular toxicity, vaccines, and even botanical drug development. The book also provides examples of both small and large molecule types with the application of functional genomics with chapters on nononcogenic drugs, oncogenic drugs, toxicometabolomics, and toxicogenomics. The remaining chapters provide practical guidance and strategies including preparation of a preclinical dossier for an investigational new drug, evaluation of preclinical safety and regulatory toxicology, the use of imaging in preclinical evaluations, and the use of various biological systems in predictive toxicology. Several other interesting chapters are included, namely, a biostatistics review of applications to case studies, the roles of study directors and study monitors, and unique systems are also examined in the areas of infusion techniques, and oligonucleotide-based therapeutics. There is a chapter on regulations and drug development in China as well as another chapter that provides an interesting case study chronology of the development of in-licensed pharmaceutical product in a small-scale biotech company.
The book presents considerable detail and highlights many old and very new relevant techniques; however, there is a paucity of information in some areas such as the development of inhalation and dermal products as well as an in-depth comparison of the European Union (EU) approach to this topic. Of the 79 contributors, 3 were from China, 3 were from Germany, and 1 was from the United Kingdom so the emphasis was definitely on the US regulations and approach to testing with probably not as much as one might have expected on the EU side in a book entitled “Comprehensive.”
Notwithstanding these issues, in sum, this book delivers on the concept of a significant resource for industrial and regulatory toxicologists in understanding the drug development process. It provides not only a terrific overview of this complex area but also provides considerable detail in many areas—some of which are still in their infancy. It is timely and on the cutting edge of drug development strategies. All in all, the book significantly contributes to the body of knowledge of drug discovery and places a great deal of that knowledge in a single source which is convenient and reasonably complete. The author recommends it highly to those involved both directly and indirectly in the drug development process as a resource and as guidance in a most complex area of biological research and development.