Abstract
This book presents a classic approach to the examination of the contributions and interactions of 4 common factors in nonclinical drug administration that contribute to the successful evaluation of therapeutics in animal models. The intention of the book, as clearly stated in the preface, is to examine these parameters as tool sets for drug delivery in order to achieve optimal exposures for the characterization of drug safety. The objectives of the book and the style of presentation reflect the extensive experience of the 2 authors, Shayne C. Gad (Principal of Gad Consulting Services) and Charles B. Spainhour (Executive Vice President and Chief Scientific Officer, Calvert Laboratories; and President and Chief Scientific Officer, Spainhour & Associates) in nonclinical pharmaceutical and device development. The book is principally divided into 2 sections, comprised of 6 and 4 chapters, respectively. The first section of the book addresses fundamental concepts regarding drug efficacy and toxicity, the pharmacokinetics, pharmacodynamics and toxicokinetics of drug exposure, and the practical mechanisms of drug delivery and dosing regimens. The focus of the second section is an exploration of chronobiology and its effects on the physiologic response to drug exposure in animal models. This is followed by a discussion of the mechanisms of nonclinical drug formulation, formulation components, and improvements in drug delivery. Broadly, the book adequately illustrates the tool sets that can be modified in order to achieve the desired selective drug delivery to animals to support subsequent administration to humans.
On first review, based on the classical textbook style of writing and review content, this book seems best suited for graduate students or new scientists who lack significant nonclinical pharmaceutical development or practical laboratory experience. On the other hand, and of extraordinary value to the experienced toxicologist, the book contains an extensive tabular index of independent formulation vehicles and excipients with specific reference to species, administration routes, doses, and toxicity for each (Appendix: Vehicles and Excipients). It is quite remarkable to have such an organized body of reference information in a single book.
The book has met each of its independent objectives with varying success. As a whole, the book lacks structural continuity and the requisite interconnections which would have allowed the reader to logically assemble the 4 independent factors into a cohesive picture. The overall presentation is varied in focus, being general and brief or detailed and extensive, often without a clear relationship to the stated focus of optimizing drug delivery in animal models. It is unfortunate that the use of figures, models, or graphs was not better exploited to illustrate concepts and to aid the reader in forming the connections as the authors intended. And unfortunately there is no more than a cursory discussion of the role of the worldwide regulatory bodies in the nonclinical pharmaceutical development process as it relates to establishing drug safety for human exposure. Without provision of at least a broad exploration of the nonclinical guidelines and regulations, the importance of the books central focus on altering formulations, routes, and regimens to improve drug bioavailability and specificity while decreasing toxicity and establishing adequate margins of safety is underdeveloped.
Despite these criticisms, the book is filled with fundamental information which may be particularly useful to the graduate student. Chapters 1 through 3 present solid introductions to the realistic challenges of the current approaches to the safety evaluation of therapeutics. These chapters address a trio of objectives (increasing systemic delivery, tolerance, and receptor delivery) and introduce basic concepts of nonclinical pharmacodynamics and toxicology. Although varying in detail across subtopics, there is adequate discussion of the components of formulation administration as it relates to absorption and the magnitude of observed effects and of the value of understanding the pharmacokinetic profiles of compounds prior to exploring their toxicity. An overview of sampling methods and data analysis is also briefly introduced. Notably, the strength of these 3 chapters is found primarily in the tabular presentation of referenced information and of standard physiologic values.
The focus of chapter 4 is on administration route as a tool set and of the potential actions that may be undertaken to improve drug tolerance within a species. Regrettably, while the amount of useful information is extensive, the presentation is disjointed. The salient points of formulation relationships to drug distribution and metabolic effects are lost in the disorganized and widely varying depth of discussion across administration routes. It is difficult to reconcile the influence of specific route characteristics with the complexity of drug absorption. However, within the chapter, there are several very useful and accessible summary tables of route-specific considerations and suggested “guidelines.” In contrast, chapter 5 is a brief but concise and organized presentation of “device” (delivery systems) with examples and tabular summary. This chapter also addresses direct application to nonclinical study design, which is a principal objective of the book. Sadly, chapter 6 is only a high-level overview of dosing regimen, a second principal point of the book, and its relationship to drug delivery optimization in the nonclinical pharmaceutical development process. A more extensive discussion of this concept and placement of the chapter after the discussion on circadian oscillations (chapter 7) as it relates to the biological response to drug administration would have been more appropriate. These 2 concepts, regimen and chronobiology, are intertwined and directly associated with the practicalities of study design.
The second section more directly turns to the stated intentions of the book beginning with an academic discussion of chronobiology. For both the graduate student and the experienced toxicologist, chapter 7 provides an excellent treatise on the links between biochronicity and physiology and biologic activities and responses as it relates to formulation development/delivery, pharmacodynamics, and toxicity. Although lengthy and highly detailed, the importance of chronobiology on formulation delivery characteristics (type and regimen), the physiologic response, and the factors that influence the pharmacokinetic/pharmacodynamic profile become clear by chapters end. Though the graduate student may find some of the information to be beyond their specific area of academic focus, the reader is left with an overall understanding of chronicity and its relationship to pharmacokinetics and drug toxicity. As previously stated, this chapter in concert with chapter 6 provides the reader with an understanding of some of the practical considerations of study design and execution.
Turning away from the more educational discussion of the previous chapter, chapter 8 brings together chemistry and drug efficacy, tolerance, and toxicity in a pragmatic context. Directly addressing formulation, one of the primary tool sets identified early in the book, this chapter clearly addresses formulation excipients and active pharmaceutical ingredient and the consideration of essential component safety. A comprehensible explanation is presented regarding the important link between formulation and administration route versus the nature and magnitude of observed effects on drug absorption and distribution, metabolism, and the factors that influence the toxicity profile. As perhaps the strongest chapter in the book, it presents the reader with a solid knowledge base of useful and directly applicable information on drug delivery, dosage calculations, material requirements and of the regulatory considerations for the independent safety evaluation of formulation excipients. The following chapter on vehicles and excipients, chapter 9, seems somewhat superfluous since much of the excipient information was already discussed. The minor amount of additional information would have been better presented within chapter 8.
Chapter 10 serves to combine the concepts and information presented in the book to this point into an integrated review as well as suggesting approaches for the improvement of selective and/or targeted drug delivery in the nonclinical setting. The organization of information in this chapter lends itself to the assimilation of the main factors or “tool sets” (regimen, device, and formulation) with administration route. Finally, here the intention of the book is most readily apparent and the authors have succeeded in summarizing the concepts of the previous chapters into more practical applications. In this context, chapter 10 is the most successful in guiding the reader toward the importance of modifying route, regimen, device, and formulation in concert in order to optimize drug delivery for the evaluation of the potential toxicity of therapeutics.
I would like to address several aspects that I consider to be significant omissions. The quality of this book suffers from a lack of editorial review that would have facilitated the effectiveness of the writing and the overall focus and integration of the objectives. This is particularly apparent in chapter 4 where the basic concepts and interrelationships were obfuscated by the disorganized style and the balance and depth of discussion across subtopics. Additionally, the organization of the book is lacking with respect to addressing the objectives in a logical progression. As the chapters advanced, there was an absence of obvious links between the primary tool sets that were introduced as critical to successful nonclinical drug administration. While I do not feel that any specific technical discussion on the aspects of drug delivery optimization in animal models is necessarily lacking, the section by section incorporation of concepts is not well developed, thus adversely affecting the general “flow” of the text. Of particular note, and as discussed above, there is only a superficial intermittent address of the global regulatory expectations for these aspects of drug delivery, study design, and safety evaluation. This is unfortunate in that the importance of the optimization of drug administration in the nonclinical environment is not effectively linked to the extrapolation of dosing to humans and the establishment of safety in the clinical setting.
Lastly, as this book seems best suited for the graduate-level student or new professional, the general absence of acronym definition on first use is troubling in that it assumes that the reader is familiar with the abbreviated terminology. Additionally, there are numerous technical errors. Among them are superfluous or repeated figures (Figures 1.2 and 1.4; Figures 4.2 and 8.3), areas of repeated text (Subcutaneous Route [SC]; pages 78 and 79); and no identification of source data for some tabular summaries referencing standard physiologic values (eg, Tables 3.5 and 3.6). And, as mentioned above, the paucity of figures, graphs, models, and illustrations is unfortunate. Their inclusion would have enriched the readers’ conceptual comprehension and effective integration of the primary parameters upon which the book is focused.
On the whole, the strengths of this book are contained within the explanations of basic concepts, the extensive reference tables and tabular summaries, and the integration of formulation, routes, and regimens as it applies to pharmacodynamics, toxicity, and safety evaluation as most effectively addressed in chapters 8 and 10. Generally, this book covers the various aspects of improving drug delivery and achieving sufficient drug exposures in the nonclinical setting in order to facilitate the evaluation of human drug safety.
I recommend this book to the graduate-level student as an introduction to the concepts pertaining to the practical aspects of drug delivery and optimization as they apply to nonclinical study design and execution. For the more experienced professional, this book provides a collective of easily referenced and organized information on formulation components and excipients as well as tabular summaries of standard physiologic and dose delivery values across nonclinical test species.