Abstract
Pharmaceutical Toxicology is an introductory textbook specifically intended to cover information relevant to the safety evaluation of drugs. The scope of this book is not meant to provide a comprehensive review of the field of toxicology, but instead intends to offer a foundation of knowledge that will provide the reader with an appreciation for the types of safety issues considered and encountered and the methodologies used to determine the nonclinical safety profile of a potential therapeutic agent. Pharmaceutical Toxicology provides an overview of basic tenets of toxicology, focuses on the specialized areas of toxicological concern, and provides knowledge around the more prominent target organ systems for toxic effect. Other aspects of the book include its coverage of the specialty area of clinical toxicology, regulatory expectations around the timing and content of nonclinical safety packages, and the concept and practice of pharmacovigilance. These topics were considered the key points of drug safety that would provide students in pharmacy and pharmaceutical sciences an appreciation for what a toxicologist in the pharmaceutical industry might consider prior to introducing a drug to the marketplace.
The first chapter takes the reader through key concepts in the field of toxicology. Routes of exposure and duration of exposure and how these relate to an effect, dose-response, or real exposure-response relationships, and safety margins and thresholds for effect are a few concepts addressed in this chapter. Each drug is understood to have its own inherent toxicity profile, dependent on a variety of factors including pharmacological mechanism of action and chemical structure. The rationale for dose selection is presented, though it should be clear that in order to fully characterize the potential toxicities of a chemical entity and put these in perspective to therapeutic use, a range of doses is applied in animal toxicity studies. The objective is to identify target organs as well as make an assessment of a no observed adverse effect level. Safety margins for observed effects can then be factored, and the nature of the lesion, inclusive of its monitorability and reversibility, can be taken into consideration in assigning a risk to benefit evaluation. Further development of discussion in this area would provide the reader with added perspective in understanding the design objectives of toxicity studies and the interpretations derived from them. Following the safety margin discussion is a review of the various types of general toxicity and specialized toxicity studies that may be included in a nonclinical safety package. The intent of these studies is clearly related; however, an important principle goes unmentioned. It should be understood that toxicity studies and the overall program are tailored to support a clinical plan (e.g., route of administration, frequency and duration of dosing).
The introduction to toxicological principles is followed by a chapter on drug metabolism, which begins with an anecdote on how perceptions of biotransformation processes as they relate to toxicity have changed with time. The purpose of metabolic enzymes and types of phase 1 and phase 2 metabolizing enzyme systems are shared along with examples of metabolic processes leading to a more toxic or reactive species that counter their original conception as purely detoxifying enzymes as well as the reverse. The potential to alter toxicity (or efficacy) profiles due to CYP induction and inhibition or secondary conjugate depletion and its consequences is conveyed, as well as the concept of phenotypic variation amongst the population that may lead to fast or poor metabolizers and how this may explain variations in response. This is followed by mention of additional topics of particular importance, including species selection for the non-clinical safety program, the potential for stereoisomers and how their toxicity profiles may vary, and the potential for drug-drug interactions.
The next chapter on molecular and cellular mechanisms of toxicity is intended to give structure to the forms of toxicity that may be encountered. The chapter includes discussion of molecular mechanisms of toxicity, forms of cellular dysfunction, types of cell destruction, and an overview of cellular responses that determine the fate of the cell. Mechanisms by which toxicity may occur, such as oxidative stress and lipid peroxidation are presented, as well as the types of cell death that may ensue. The cellular dysfunction section briefly mentions the potential for up-or down-regulation of protein synthesis subsequent to a toxic insult. The field of toxicogenomics would have been appropriate to introduce, given the increasing application of technologies such as DNA microarrays to gather information on cellular responses to toxicity.
Chapter 4 is the first of three chapters that deal with specialty areas of toxicology, covering teratology, genotoxicity, and carcinogenicity. The teratology chapter places emphasis on examples of teratogenic agents, including the classic thalidomide and diethylstilbestrol examples, as well as a more contemporary description of the potential relationship between cardiovascular malformations and hERG inhibition. Although these examples convey the importance of sensitive and predictive assays for screening compounds for teratogenic effects, greater attention could have been given towards developing those topics that would provide the reader with a more solid foundation of the principles of developmental toxicity. The factors that may determine human relevance of teratogenic signals, for instance, are presented as a list of questions for which the answers would have offered valuable insight. Unlike the following chapters covering specialty areas, this chapter did not provide details on the methodology used to evaluate for teratogenic potential or discuss the potential application for in vitro screening models earlier in discovery drug development for those therapeutic areas where reproductive toxicities would not be tolerated.
This next chapter on genotoxicity provides a clear introduction to the types of end points that may arise from exposure to a genotoxicant, followed by a description of the types of assays that are used in their detection. Chapter 1 presented the concept of thresholds and touched on conditions where thresholds may not apply. The acceptability of relating a threshold relationship to genotoxic effects is illustrated here with the paracetamol example where regulators viewed the chromosomal damage observed in vitro and in vivo as a threshold effect. The paracetamol example illustrates how knowledge around the mechanism of toxicity can sometimes satisfactorily explain a genetic toxicity finding and allow for a threshold assessment. The chapter wraps up with the practical aspect of incorporating genotoxicity testing earlier as part of a discovery drug development strategy. This chapter is logically followed by that on carcinogenicity.
Chapter 6 takes a limited approach towards the content, where there was a brief introduction to key concepts of carcinogenicity, such as malignant versus benign growth, the concept of the three-step process of carcinogenesis, and epigenetic mechanisms of carcinogenicity. This was followed by topics pertinent to drug development; including considerations for when carcinogenicity studies should be conducted and description of the traditional 2-year chronic bioassay design that is used to identify carcinogenic potential. A great example is given of a change in regulatory expectation for carcinogenicity assessment based on advances in available treatment. Once considered a life-threatening condition, with the advent of new and effective drugs that extend the life span of AIDS individuals, expectations for completion of carcinogenicity assessments have shifted along with it. This example relates a key concept of how the nonclinical safety program requirements are a reflection of a drug’s intended use. Details on the use of transgenic mouse models could have been developed more fully because such approaches may be regulatory acceptable under certain circumstances.
The next four chapters cover the more prominent organ systems that may have greater exposure to potential toxicants as a result of the administration route or organ function. The first of these chapters, on the liver, provides a clear introduction to the characteristics of the organ, including structure and function that relate to its susceptibility to drug-induced toxicity. The regenerative capacity of the liver is conveyed during the course of covering the types of liver toxicity and examples of liver toxicants. The acetaminophen example illustrated several important principles related to biotransformation processes in this organ, such as the potential for and consequences of metabolic enzyme depletion and an understanding for regionally localized toxicity based on inherent distribution of enzymes. Of particular importance was the introduction of the concept of safety biomarkers. In this case, elevations in transaminases were identified as indicators of liver toxicity and therefore a means for monitoring in both animals and humans.
Again, the author of the following chapter on the kidney offers insight on the vulnerability of this organ, relating the sensitivity to ATP depletion and exposure to drugs and their metabolites due to its excretory function. The nephron components are described, providing a general impression of the processes that takes place. The primary focus is placed on the proximal tubule. Conditions that make the proximal tubule the primary site of nephrotoxicity are related, and its regenerative capabilities are shared which conveys the potential reversible nature of such changes. Again, the inclusion of clinical chemistry and urinalysis measurements as parameters that can be monitored as safety biomarkers for renal toxicity is an informative section. The lack of sensitivity of these biomarkers, however, is an issue, and metabolomics is introduced as a novel approach that may assist in the identification of new markers for earlier indication of kidney toxicity.
The respiratory toxicity chapter follows in similar fashion, first providing details on the structure and function of the respiratory system and mechanisms by which toxicity occurs in this organ, before sharing the forms by which toxicity is observed and examples of toxicants that inflict such damage. Although interesting differences between humans and rodent species are shared in the discussion of methods for studying respiratory toxicity, an explanation is lacking for how this information is managed during the interpretation of data for risk assessment. Additional attention could also have been introduced on study design considerations that are unique to inhalation toxicology studies, such as whether species differences in the respiratory tract are considered in selection of the toxicology species, the use of nose-only apparatus versus whole-body exposure systems, and factors that determine the maximum administrable dose.
The final chapter on organ systems covers immunotoxicity. The players of the immune system and their function are first introduced, along with a brief description of acquired and innate immunity. Mechanisms by which immunosuppression occur are then covered as well as a cursory mention of immune enhancement. A large portion of the chapter and the greatest amount of detail is provided on immune-mediated diseases, hypersensitivity, and autoimmunity. Finally, the means for assessing immune function are addressed, which provides a good understanding of the tiered approach to evaluating for immunotoxic potential. The possibility for a stress-related, indirect effect on the immune system and the factors that may enable such an interpretation were not addressed. Insight into the mechanism and toxicity profile (hematological and histopathological changes for instance) that may enable this assignment would have been informative. In addition, the occasional reference to biotechnology-derived products in other chapters is noticeably absent here.
The introduction of toxicological principles and common target organ systems of toxicology then bring a chapter covering clinical toxicology. This chapter specifically addresses the forms in which poisonings occur (acute versus chronic, mechanisms, circumstances, and preventive measures), means of diagnosing the poison, treatments and antidotes, and examples of commonly encountered drug poisonings. Although the chapter is well written and the subject matter is of relationship to pharmaceuticals, the focus of this chapter is not consistent with the book’s objective of introducing the student to issues relevant to the assessment of nonclinical safety of new drugs.
Chapter 12 distinguishes this book from the standard textbook on toxicology with its coverage of regulatory expectations around pharmaceutical drug development. This chapter provides a well-rounded introduction to the regulatory landscape for the nonclinical safety assessment of drugs. The chapter first begins by defining the European regulatory environment and acknowledges the US equivalent, then introduces the International Conference of Harmonization (ICH) and the intent of GLPs. An emphasis is made towards placing nonclinical safety in perspective with therapeutic efficacy with the weight of the balance defined by the therapeutic indication. This concept is an important one to convey, that even a genotoxic finding may be acceptable for use given a life-threatening condition, but a blood pressure effect, although monitorable and reversible, might represent an unsuitable side effect of a sleeping pill. As the assessment of safety continues, unfortunately, the explanation for the basis of safety margin calculation may be lost on the reader that has no formal understanding of an AUC, as this is the first introduction to this terminology in the book. Discussion of how the nonclinical safety information is used to calculate the starting dose for the first in human (FIH) trial would have been informative, and though it is implied, there is no direct mention of how clinical monitoring is driven by the safety findings identified from nonclinical studies. Nonetheless, the purpose of animal toxicity studies and their timing in relationship to the clinical development process is nicely presented. This chapter is comprehensive in its coverage of the regulatory realm, introducing nontraditional FIH testing strategies, which in the right situation could allow faster and more efficient drug development to take place, as well as addressing issues and testing approaches specific to biotechnology products and vaccine development. Before the lead-in to postmarketing surveillance, the predictive value of animal studies is also addressed, a question that undoubtedly arises as the reader progresses through the chapters on target organ toxicities.
The term pharmacovigilance and the importance of what it represents is not a prominent topic of drug safety evaluation. The assumption may be that by the time a drug is on the market its safety profile would be fully characterized. This chapter on pharmacovigilance is informative as to the categories under which adverse events may fall and the forms of adverse event reporting. Through its description of the process for assessing the data, the factors that may influence the ability to ascertain the drug relationship are readily apparent. The need for continued efforts to standardize the reporting process and create centralized systems is clear.
Pharmaceutical Toxicology provides a sound background of knowledge with appropriate content and level of detail for the pharmacy or pharmaceutical sciences student to develop a basic understanding of the general approach taken towards evaluating the safety profile of a potential new medicine, the types of issues that may be encountered, and some perspective on how risks are managed. Although it is understood that this book would not be comprehensive in addressing all potential forms of toxicity, one important omission from the target organ coverage was the cardiovascular system. There were also occasional references to a European versus a more inclusive global viewpoint, reflecting the European influence of the authors. Given that this book is likely to have a wider audience, it would have been appropriate to reference the ICH guidelines (as introduced in Chapter 12) or offer where differences in expectation exist. In addition, although the book relates how the therapeutic need influences the degree of risk tolerance and creates a risk-to-benefit balance, the point should also be made that the form in which toxicity presents itself, not only its associated safety margins but also whether monitorable and reversible, will also factor into the overall assessment of risk that will drive development decisions.