Abstract
If you are a toxicologist and reading this review, hopefully it is because of the importance of the first 2 words in the title of the book. For those toxicologists who may have elected to pass on taking a closer look at the book because of the last 2 words of the title, how loud do I have to shout for you to reconsider? If you are still unmoved, try substituting the most appropriate word that describes your area of practice in toxicology, for example, pesticides, consumer products, food additives, and so on, for “drug.” If you assume the book is about pharmaceuticals, think again.
If you suspect the book is exclusively about in vitro assays or alternatives to animal testing, you will be disappointed. The central issue conveyed in the book is efficiency and productivity in executing toxicology for assessing human health risk. Drugs or pharmaceuticals are only the vehicle or platform describing how the work of toxicology is being transformed and some of the horizons to which it can navigate.
The 2 editors and their 39 contributing authors present 19 chapters in 2 sections: (1) Specific Areas of Predictive Toxicology; and (2) Integrated Approaches of Predictive Toxicology. There are 9 and 10 chapters, respectively, in the 2 sections. The first section provides topics pointing where, and to a lesser extent how, the prediction of toxicity is achieved. The second section continues in demonstrating the where and how of toxicological predictions, but there is a shift in the emphasis between the 2 when compared to the first section. In addition, there is an unfolding of how the integration of predictive toxicology occurs in drug developments. If you are beginning to suspect, based on the recurring phrase “predictive toxicology,” that the book is about anticipating adverse biologic events resulting from xenobiotics, you are correct.
The first of the book’s 2 sections has an initial 17-page chapter entitled “The Human Predictive Value of Combined Animal Toxicity Testing: Current State and Emerging Approaches,” which sets the stage for the book. The authors of the chapter effectively describe the drug development process from discovery to clinical trials along with where and how animal toxicity testing contributes to predicting human toxicity. The authors draw upon their often-quoted publication, describing the correlation of animal and human toxicities. 1
Chapters 2, 3, 4, 7, 8, and 9 comprise slightly more than 40% of the book and address target organ or system toxicities. The topics covered in these chapters include genetic toxicity, cardiac safety, liver injury, immunotoxicity, neurotoxicity, and the adverse effects resulting from xenobiotics observed in developmental biology. It is obvious that these topical areas were carefully selected since these toxicities, historically, have been troublesome because they show up late in drug developments, or worse yet, after the drug is marketed.
Chapter 4, “Predicting Drug-Induced Liver Injury—Safer Patients or Safer Drugs?” is noteworthy for several reasons. Drug-induced liver injury (DILI), according to the author, accounts for 50% of all acute liver failures and is responsible for 5% of all hospital admissions. Second, DILI is idiosyncratic and not all the patients receiving a particular drug are at risk of liver toxicity. Consequently, the condition or predisposition of the patient plays a role in the toxic response.
The author discusses the risk of DILI from toxicokinetics and toxicodynamic perspectives. Integrated approaches for predicting DILI are presented, which include toxicokinetic factors as well as ways to assess the mechanism of liver toxicity resulting from multiple factors such as multihit and multistep processes. As a result, prediction of DILI requires an integrated approach in which not only the drug is under consideration but also the condition of the potential patients.
It is remarkable that in the 9 chapters in the book’s first section, written independently by 14 authors, 2 underlying threads or subtle themes recur in various forms: (1) following regulations and regulatory guidance alone is not adequate to either control developmental costs or provide needed medicines; and (2) predictive toxicology in the form of screens, assays, and tests results in both early termination of nonviable drug candidates and consequently increases the likelihood of clinical efficacy of the candidate that is ultimately selected. The consistency of the expression of these 2 threads, albeit veiled at times, speaks to their validity. More importantly, predictive toxicology information results in better informed clinicians and patients, who are alerted to potential adverse effects.
The second section of the book, entitled “Integrated Approaches of Predictive Toxicology,” is approximately half of the book and has 10 chapters (Chapters 10-19). While the first section of the book describes early prediction of toxicity, the second section describes how to integrate or incorporate early indicators of toxicity into drug development. However, all of the integrative approaches can validly apply to materials other than drugs.
Chapter 10, entitled “Integrated Approaches of Predictive Toxicology,” makes a strong case for incorporating absorption, distribution, metabolism and excretion (ADME) studies early in the drug development process. The position advocated by the authors transforms the erroneous perception that toxicologists are naysayers who kill products at the end of the development process into contributing stakeholders who help define target selection and lead optimization. The net effect is reduced costs and an increased success rate for drug candidates. What a novel idea!
There are collateral benefits to this enlightened view of using ADME as a means to optimize lead candidate selection. The early use of ADME provides the springboard to launch a toxicology program specifically directed at the best lead candidate. ADME and toxicology can assist in picking the best candidate for development. In addition, early incorporation of ADME with target identification and lead optimization can improve the quality of in vivo toxicity testing by providing guidance in protocol development for the toxicology studies. Furthermore, there is the potential for reducing the number of false positives and negatives resulting from in vitro assays that attempt to describe either efficacy or adverse effects. Wait a second—efficacy? Yes you read that right and it is another novel idea: toxicology assisting in establishing efficacy.
Chapter 11, “Predictive Toxicology Approaches for Small Molecule Oncology Drugs,” describes the opportunity to reduce morbidity and mortality, especially for drugs that treat cancers that are detected early. In the past, the approach for small molecule therapies for cancer treatment has been to assault the disease early and aggressively with toxic chemotherapeutic agents. The adverse consequences to the patient were obvious and significant since cancer chemotherapeutic agents, by their very nature, are toxic. The authors suggest a paradigm for developing cancer drugs that is not dissimilar to the approach described in Chapter 10. However, there is the additional opportunity for the toxicologist to assist in defining and managing adverse effects in the clinic.
Chapter 12, “Mechanism-Based Toxicity Studies for Drug Development,” is noteworthy since the authors make a case for conducting mechanism-of-toxicity studies. In advocating mechanistic toxicity studies, the authors expand and develop the approach outlined in Chapter 10. The authors conclude that mechanistic studies in toxicology, which are part of the early development process, can assist the development in 2 ways by (1) establishing the viability of a particular approach for therapeutics development; and (2) validating lead identification and optimization.
Chapters 13, 14, and 15 discuss specific models and approaches for detecting adverse responses early in the drug development process. The focus of Chapter 13 is on fish embryos with specific attention to zebra fish. The authors point out that the potential for the fish embryo in rapid screening beyond reproductive effects is considerable. As the model is developed, the specificity and limitations in screening for nonreproductive effects will be more clearly understood.
Chapters 14 and 15, unlike Chapter 13, are focused on models that contribute to the elucidation of the mechanism of toxicity rather than providing rapid screening tests. Chapter 14 discusses the role of genetically modified mouse models, and Chapter 15 addresses toxicogenomics and pathway analysis. While some of the screening procedures described in Chapter 15 are rapid, it may well be the real value of genetically modified mouse models will lie in the validation of testing procedures used in other assays.
“Drug Safety Biomarkers” (Chapter 16) describes the current status of these tools for assessing toxicity in preclinical studies. The authors point out that biomarkers can be used to point out early indications of toxicity and their use can be, in certain circumstances, a validation of histopathologic diagnoses. In addition, biomarkers can often give insight into the mechanism of toxicity. Finally, the authors point out the distinct advantage of biomarkers having the potential of carryover into the clinic to monitor patients receiving a particular drug. However, such clinical carryover requires regulatory acceptance.
Chapter 17, “Application of TK/PD Modeling in Predicting Dose-Limiting Toxicity,” brings into focus a new way of looking at the approaches presented and discussed in many of the previous chapters related to the time course of the toxicity or toxicokinetics (TK) of a drug in the context of the drug’s therapeutic benefit or pharmacodynamics (PD). The model described in the chapter attempts to link binary toxicity responses, for example, tissue lesions and mortality with TK metrics, which is slightly different than routine pharmacokinetics/pharmacodynamics (PK/PD) modeling in pharmacology studies that analyze PK metrics to single responses or a single end point. The TK/PD model that is described may be a new and perhaps better way of looking at Therapeutic Index.
Chapter 18, “Prediction of Therapeutic Index of Antibody-Based Therapeutics,” provides, at least for biologic drugs and specifically monoclonal antibodies (mAbs), a slightly different approach for increased drug development efficiency. Using a mechanistic mathematical model for mAbs, the authors suggest a way for predicting efficacy early in the development of a candidate therapeutic. Early modification of mAbs can be made at a point in the development when investment is low, that is, economic efficiency, resulting in increased efficacy and a reduced probability of failure in the clinic. Unlike many other approaches, methods, tests, and assays, which are aimed at identifying toxicities early and then developing strategies to mitigate the toxicities, the authors propose an approach using mathematical modeling that shifts the therapeutic index in favor of increased efficacy. In theory, at least, increased efficacy and reduced toxicity have the potential for reducing the failure rate in the clinic. The important message of Chapter 18 lies in a process of bringing efficacy and toxicity assessments closer together.
The 19th and final chapter, “Vaccine Toxicology: Nonclinical Predictive Strategies,” is mostly directed at the hazard identification and risk assessment process for vaccines. The authors state that in vitro predictive models were reviewed previously and cite references for the reader. The authors describe a new predictive system that they call “Molecular Immune in vitro Construct Technology System (MIMIC). However, only 1 reference was cited and the authors' description of the system is inadequate to provide guidance for its implementation.
If “n” number of toxicologists were asked to define “predictive toxicology,” it is possible to get n + 1 to 2n number of different responses, of course depending upon the sample size. It is not that toxicologists do not know what they are doing; it is because the phrase “predictive toxicology” is amorphous and is perceived differently by individual toxicologists.
There are many opinions as to why there is a diverse understanding of what exactly “predictive toxicology” is. While most everyone would agree that the number of variables for predicting toxicity is large, the universal constant is the end point, which is human safety and the reduction in toxicological risks to humans. The editors use a platform of drug development to describe their view of “predictive toxicology”; however, the materials and methods, results and discussions have standing in nonpharmaceutical toxicology and human risk assessments. Consequently, the book is not limited in its utility to pharmaceutical industry toxicologists.
The editors and chapter authors take what is an open-ended topic and apply a laser focus and a scrupulous intention of staying on topic to create a valuable treatise of less than 400 pages. To be sure, some toxicologists may feel slighted because their isolated corner of the toxicological sandbox is not covered, but the editors elected to treat a focused set of topics well rather than cover many topics poorly. The editors and chapter authors assume that the reader is an experienced toxicologist who is beyond the fundamentals of toxicology and who is looking for ways to anticipate and preempt adverse responses seen using classical toxicological methods. Putting Predictive Toxicology in Drug Safety in perspective with other treatises on toxicology and using the paradigm of Miller Analogies from psychological testing: Casarett & Doull’s Toxicology is to introduction as Predictive Toxicology in Drug Safety is to advanced.
Much of the information contained in the book is scattered throughout the literature that toxicologists use. In addition, many of the chapter authors are the leaders or at least noteworthy contributors to those toxicologically important research areas. These facts and circumstances do not diminish the relevance and importance of the book. On the contrary, the book provides a valuable contribution to practicing toxicologists, inside or outside the pharmaceutical industry, by giving collected or focused technical information while at the same time paving the way for toxicologists to increase their efficiency, both in their practice and in the economic environment in which they carry out their activities.