Abstract
This is an extremely comprehensive book on the practice of toxicology in nonclinical drug development, with a total of 35 chapters broken into 8 sections contributed by 75 scientists from the United States (the predominant country of contributors), China, Germany, and the United Kingdom. The contributors are employed in a variety of consulting practices, small and large contract research organizations, and small and large pharmaceutical companies and are all experienced and knowledgeable in their fields.
The first edition of this book was published in 2013 and was reviewed by International Journal of Toxicology 1 and was very well received in this and other similar reviews. Given the rapid advances in several areas of toxicology as they relate to drug development, this second edition is timely. The content has been updated, with several chapters consolidated and reorganized. In addition, new chapters have been added on the topics of biomarkers, medical devices, nonclinical safety assessment of cell-based therapies, and concepts, strategies, and pitfalls in nonclinical drug development. These additions are welcome as these areas of drug development have received a significant amount of attention over the past 4 years and should continue to be areas of high interest.
The chapters are organized into 8 general areas: drug discovery, metabolism, and pharmacokinetics; toxicology studies and IND application and first-in-human clinical trial; clinical pathology, histopathology, and biomarkers; biostatistics, regulatory toxicology, and role of study directors; specialty route of administration; nonclinical development of monoclonal antibodies, stem cells, oncogenic and nononcogenic drugs, oligonucleotides, and vaccines; safety evaluation of ocular drugs, botanical products, and medicinal devices; and predictive toxicology, toxicometabolomics, toxicogenomics, and imaging. The chapters included in each section are in general well written, with comprehensive references and clear illustrations. Sufficient detail is given to provide the reader with a clear understanding of the subject matter, with some chapters going into greater detail than others.
Comments by individual chapters are as follows:
Chapter 1 (A. S. Faqi) is a general introduction to the overall drug development process and a general description of the rest of the book. Chapter 2 (E. Koch and S. Plassmann) describes the basics of dose selection for toxicity studies for both small molecules and biopharmaceuticals and provides examples of issues that can arise during drug development programs, including hepatotoxicity, cardiotoxicity, genotoxicity, and carcinogenicity, as well as examples of reproductive toxicity. Chapter 3 (J. Vrbanac and R. Slauter) provides an overview of Absorption, Distribution, Metabolism and Excretion (ADME) throughout the drug discovery process, typically leading up to the Investigational New Drug application (IND) but during the drug development process as well. Basic concepts are discussed, and a nice overview of drug transporters involved in absorption is also provided. Metabolism in hepatic microsomes, including analysis of cytochrome P450 isozymes, is also discussed, as well as the implications for drug–drug interactions. The chapter also summarizes some of the key methodologies used in these analyses. Chapter 4 (M. Schrag and K. Regal) details concepts and calculation used in pharmacokinetics and toxicokinetics, including analysis of intravenous dosing, extravascular dosing, and calculation of exposure-based safety margins. The authors also provide an overview of practical considerations when conducting and interpreting pharmacokinetic and toxicokinetic studies that may significantly affect the data, such as dosing volume, fed versus fasted animals, site of blood sampling, and dose linearity versus dose proportionality. Specific information on dosing volumes by route in various nonclinical species is a welcome inclusion to the chapter.
The second section of the book (chapters 5-13) deals with the design and execution of studies that are typically included in an IND-enabling toxicology study, as well as an overview of development of a preclinical dossier to support first-in-human clinical trials. The topics include acute, subacute, subchronic, and chronic general toxicity testing for preclinical drug development (chapter 5: K. H. Denny and C. W. Stewart), genetic toxicology testing (chapter 6: J. Nicolette), safety pharmacology assessment (chapter 7: T. J. Baird, D. V. Gauvin, and J. A. Dalton), preparation of a preclinical dossier to support an IND application and first-in-human clinical trial (chapter 8: P. Nugent, J. N. Duncan, and D. B. Colangiovanni), developmental and reproductive toxicology (chapter 9; A. S. Faqi, A. Hoberman, E. Lewis, and D. Stump), immunotoxicology assessment (chapter 10: J. T. Farmer and R. R. Dietert), juvenile testing (chapter 11: A. S. Faqi), preclinical evaluation of carcinogenicity (D. L. McCormick), and current strategies for abuse liability assessment of new chemical entities (D. V. Gauvin, J. A. Dalton, and T. J. Baird). The sections are well written and up to date. It is not clear why the chapter on preparation of the preclinical dossier is placed in the middle of the section, when it would seem to be more appropriate to place it after the other sections with the specific toxicology topics, given that the dossier is used to summarize all of the various pieces of information. In addition, in chapter 8, the authors suggest that writers of toxicology summaries in an IND written in the Common Technical Document (CTD) format may not want to include key protocol information (eg, experimental study design details) as this information is also provided in a CTD tabulated summary. However, since tabulated summaries are required for New Drug Applications but tabulated summaries are not always included in INDs, it may in some cases be advisable to use more complete summaries in module 2 toxicology summary sections to assist the reviewer in their analysis.
Section 3 deals with clinical pathology, histopathology, and biomarkers, which are covered in chapters 14 (Clinical pathology; M. J. York), 15 (Best practice in toxicological pathology; M. M. Abdi), 16 (Molecular pathology; L. Oyejide, O. R. Mendes, and I. Mikaelian), and 17 (Biomarkers in nonclinical drug development; A. D. Aulbach and C. J. Amuzie). The use of colored photomicrographs to depict various typical toxicities in different organs was used well, and the discussion of biomarkers, including applicability and the emergence of new biomarkers for major organ toxicities, included the challenges faced with establishing new biomarkers.
Section 4 deals with biostatistics (chapter 18: T. Vidmar, L. Freshwater, and R. Collins), regulatory toxicology (chapter 19: J. W. Kille), and the role of study directors (chapter 20: S. Frantz and C. Johnson). The case studies in the chapter on biostatistics were well selected to highlight various issues that can arise with different types of toxicology studies. The chapter on regulatory toxicologist also used good examples of the evolution of the field and the necessity of toxicological assessment throughout the drug development process, including labeling of new products. The chapter on the role of study directors included some extremely useful checklists on roles and responsibilities that have been the subject of discussion for many years and are a necessary part of the training of anyone who will either monitor or be responsible for the conduct of studies.
Section 5 deals with specialty routes of administration and includes chapter 21 on infusion toxicology and techniques (J. C. Resendez and D. Rehagen) and chapter 22 on photosafety assessment (D. B. Learn, P. D. Forbes, and C. P. Sambuco). Both chapters detail regulatory and technical aspects of their subject matter and include pertinent graphs and tables illustrating key data that make the chapters easy to follow. An important omission from this section is a separate chapter on topical dosing/dermal toxicology, which is becoming more widely used as the pipeline of dermal drug development projects has grown significantly over the past few years. There is a small amount of information on topical dosing in other chapters, but the information is not readily available and not covered in depth.
Section 6 deals with nonclinical development of monoclonal antibodies (chapter 23, K. B. Meyer-Tamaki), stem cells (chapter 24, C. J. Amuzie and A. Faqi), oncogenic and nononcogenic drugs (chapter 25, J. B. Colerangle and chapter 26, H. H. Oh, S. Surapaneni, and J. Y. Hui), oncology drugs (chapter 26, H. H. Oh, S. Surapaneni, and J. Y. Hui), vaccines (chapter 27, M. D. Green and N. H. Al-Humadi), and an overview of nonclinical development strategies and class effects of oligonucleotide-based therapeutics (chapter 28, H. S. Younis, M. Templin, L. O. Whiteley, D. Kornbrust, T. W. Kim, and S. P. Henry). These chapters are fairly comprehensive on their individual subject matters, and good examples are provided on potential toxicological concerns for the various protein-based therapies. Chapter 25 is unusual as it is a summary of information contained in previous chapters on small molecule development, which is not necessary for this section of the book, and does not go into depth on the development of large molecules, a significant omission for the text as the development of proteins other than monoclonal antibodies is a large and growing percentage of therapeutic products under development. In addition, chapter 25 appears to be the only chapter with a discussion of the toxicological assessment of impurities, a key consideration in safety assessment of pharmaceuticals.
Section 7 describes the safety evaluation of ocular drugs (chapter 29, M. Ferrell Ramos, M. Attar, M. E. Stern, J. A. Brassard, A. S. Kim, S. Matsumoto, and C. Vangyi), botanical products (chapter 30, A. S. Faqui and J. S. Yan), and medical devices (chapter 31, N. S. Gould). Chapter 30 on botanical products as written describes regulatory expectations but would have benefitted from providing some examples of successful and problematic development programs. The chapter on medical devices does a good job covering the regulatory expectations associated with safety assessment of devices and does mention other considerations such as the safety assessment of eluting components as well as elution of trace elements and metals.
Section 8 discusses computation and biological platforms for chemical safety assessment (chapter 32; R. S. Settivari, J. C. Rowland, D. M. Wilson, S. M. Arnold, and P. J. Spencer), toxicometabolomics (chapter 33; M. V. Milburn, J. A. Ryals, and L. Guo), toxicogenomics (chapter 34; T. C. Fuchs, G. L. Truisi, and P. G. Hewett), and imaging used for preclinical evaluation (Chapter 35; Z. J. Wang, T-T. A. Chang, and R. Slauter). Each of these chapters include very illustrative examples of the applications of the various technologies, as well as potential future directions. Given the growing complexity of drug development projects, more extensive investigative efforts to understand the nature and significance of toxicological effects observed both in early toxicology studies and in the clinic, both premarketing and postmarketing, have been required and will undoubtedly grow in importance.
Overall, this text pulls together a large variety of disparate disciplines and information to provide a nice guide to understanding the role of toxicology in drug development and should serve as an excellent reference for both novice toxicologists and more experienced hands involved in drug development. I highly recommend it, this is a book that should be on the shelf for anyone involved in nonclinical drug development.