A Comprehensive Guide to Toxicology in Nonclinical Drug Development

Ali S. Faqi

• Publisher: Academic Press
• Year: 2016
• ISBN:
  9780128036211
• Edition: 2
• Topic: Medicine
• Subtopic: Toxicology

A Comprehensive Guide to Toxicology in Nonclinical Drug Development, Second Edition, is a valuable reference designed to provide a complete understanding of all aspects of nonclinical toxicology in the development of small molecules and biologics. This updated edition has been reorganized and expanded to include important topics such as stem cells in nonclinical toxicology, inhalation and dermal toxicology, pitfalls in drug development, biomarkers in toxicology, and more.

Thoroughly updated to reflect the latest scientific advances and with increased coverage of international regulatory guidelines, this second edition is an essential and practical resource for all toxicologists involved in nonclinical testing in industry, academic, and regulatory settings.

• Provides unique content that is not always covered together in one comprehensive resource, including chapters on stem cells, abuse liability, biomarkers, inhalation toxicology, biostatistics, and more
• Updated with the latest international guidelines for nonclinical toxicology in both small and large molecules
• Incorporates practical examples in order to illustrate day-to-day activities and the expectations associated with working in nonclinical toxicology

Chapter 1

Introduction

A.S. Faqi

Abstract

Drug development is defined as the entire process of bringing a new drug or device to the market. It involves discovery and synthesis, nonclinical development (chemical testing, biological testing, pharmacology, toxicology, safety, etc.), clinical development (Phase I–III), regulatory review, marketing approval, market launch, and postmarketing development.

Keywords

New Chemical Entity (NCE); Nonclinical testing; No-Observed-Adverse-Effect-Level (NOAEL); Optimization; Toxicogenomics; Toxicometabolomics

Drug development is defined as the entire process of bringing a new drug or device to the market. It involves discovery and synthesis, nonclinical development (chemical testing, biological testing, pharmacology, toxicology, safety, etc.), clinical development (Phase I–III), regulatory review, marketing approval, market launch, and postmarketing development (Fig. 1.1).

The process of drug discovery comprises research on (1) target identification, (2) target prioritization/validation, (3) lead identification, and (4) lead optimization.

A range of techniques is used to identify and isolate individual drug targets. The target identification process isolates drugs that have various interactions with the disease targets and might be beneficial in the treatment of a specific disease. A poor understanding of the molecular mechanisms underlying both disease progression and drug action is one of the major challenges of drug discovery as insufficient drug specificity and side effects are often discovered during the late stages of drug development or even after marketing approval [1]. A “target” can be either proteins physically binding to the drug or to proteins that are only functionally related. A decent target needs to be efficacious, safe, meet clinical and commercial needs, and, above all, be “druggable” [2]. On binding, a druggable target elicits a biological response that may be measured both in vitro and in vivo as the putative drug molecule, be that of a small molecule, or biologicals is accessible to the target [2].

Identification of drug target is followed by a target prioritization/validation phase, during which experimental tests are conducted to confirm that interactions with the drug target are associated with the desired change in the behavior of diseased cells. It is the process by which the predicted molecular target of a drug is verified. The following criteria serve as decision-making tools prior to advancement beyond target validation [3]:

1. Known molecules modulating target

2. The target has a history of success

3. Genetic confirmation

4. Availability of known animal models

5. Availability of low-throughput target validation assay that represents biology

6. Intellectual property of the target

7. Determination of the marketability of the target

The next phase following target validation is obviously the lead identification. Identification of lead compounds are sometimes developed as collections, or libraries, of individual molecules that possess the properties required in a new drug. Once the lead is identified, experimental testing is then performed on each of the molecules to confirm their effect on the drug target. This progresses further to lead optimization. Lead optimization studies are conducted on animals or in vitro or modulation of a desired target in disease patients [2] to compare various lead compounds, to determine how they are metabolized, and what affect they might induce in the body. The information obtained from lead optimization studies helps scientists in the pharmaceutical industry sort out the compounds with the greatest potential to be developed into a safe and effective drug [2].

Toxicology studies in the drug discovery process are conducted to evaluate the safety of potential drug candidates. This is accomplished using relevant animal models and validated procedures. The ultimate goal is to translate the animal responses into an understanding of the risk for human subjects. This demands additional studies and investment earlier in the candidate evaluation, coupled with an arduous selection process for drug candidates and a speedy kill to avoid spending money and time on compounds that would likely fail in development.

Even after a successful drug candidate for a disease target is identified, drug development still faces enormous challenges, which many drugs fail because of their unacceptable toxicity. The new paradigm in drug discovery should consider a vigorous means of identifying issues related to toxicity early in the discovery process where the cost of a failed drug is far less than in late drug development stages [4].

Figure 1.1 Drug development and nonclinical testing process.

The successful drug candidate undergoes a nonclinical safety-testing program. Key factors affecting the type of nonclinical testing include the chemical structure, nature of the compound (small molecules or biologics), proposed human indication, target population, method of administration, and duration of administration (acute, chronic). During nonclinical drug testing, the toxicity and pharmacologic effects of the new chemical entity (NCE) are evaluated by in vitro and in vivo laboratory animal testing. An investigations on drug absorption and metabolism, toxicity of the drug’s metabolites, and the speed with which the drug and its metabolites are excreted from the body. Investigational new drug application (IND)-enabling safety studies include acute toxicity of the drug in at least two species of animals, and short-term toxicity studies ranging from 2 weeks to 1 month, genotoxicity, safety pharmacology, and bioanalytical. Furthermore, post-IND nonclinical testing may include subchronic, chronic toxicity, developmental, and reproductive toxicology and carcinogenicity.

It is estimated that it takes 10–12 years to develop and test a new drug before it can be approved for clinical use. This estimate includes early laboratory and animal testing as well as later clinical trials using human subjects. A new study by the Tufts Center for the Study of Drug Development estimates the cost of developing a new drug that gains marketing approval to be around $2.6 billion [5]. Safety issues are the leading cause of attrition at all stages of the drug development process. It is important, however, to understand that the majority of safety-related attrition occurs preclinically, suggesting that approaches that could identify “predictable” nonclinical safety liabilities earlier in the drug development process could lead to the design and/or selection of better drug candidates with increased chances of succeeding for marketing approval [6]. An overview of drug discovery screening assay is shown in Fig. 1.2 [2].

Toxicology testing in animals traditionally focus on phenotypic changes in an organism that result from exposure to the drug; therefore efficient and accurate approaches to assess toxicological effects of drugs on living systems are still less developed. One of the key factors used for a go/no-go decision-making for an NCE relies on the early knowledge of any potential toxic effect. Thus the traditional approach based on the determination of the No-observed-adverse-effect-level (NOAEL) is far from accurate. One of the limitations of this approach is that it may fail to detect adverse effects that manifest at low frequencies.

Indeed, in the past quarter of a century new technologies have emerged that have improved current approaches and are leading to novel predictive approaches for studying disease risk. Increased understanding of the mode of action and the use of scientific tools to predict toxicity is expected to reduce the attrition rate of NCE and thus decrease the cost of developing new drugs. In fact, most big pharmaceutical companies are now using improved model systems for predicting potential drug toxicity, both to decrease the rate of drug-related adverse reactions and to reduce attrition rates. A wide range of biological assay platforms, including toxicogenomics and metabolomics employed in constructing predictive toxicity, are included as separate chapters in this book. The discipline of toxicogenomics is defined as the application of global mRNA, protein and metabolite analysis-related technologies to study the effects of hazards on organisms [7]. Examining the patterns of altered molecular expression caused by specific exposures can reveal how toxicants act and cause their effect. Identification of toxicity pathways and development of targeted assays to systematically assess potential mode of actions allow for a more thorough understanding of safety issues. Indeed, there is high expectation that toxicogenomics in drug development will predict/better assess potential drug toxicity, and hence reduce failure rates.

Figure 1.2 Overview of drug discovery screening assay. Hughes JP, Rees S, Kalindjian SB, Philpott KL. Principles of early drug discovery. Br J Pharmacol 2011;162(6):1239–49.

In addition metabolomics, a more recent discipline related to proteomics and genomics, uses metabolic signatures to determine the molecular mechanisms of drug actions and predict physiological toxicity. The technology involves rapid and high throughput characterization of the small molecule metabolites found in an organism, and is increasingly gaining attention in nonclinical safety testing. Moreover, the introduction of pharmacogenetics assays has also brought success in drug development in terms of predictability of safety and efficacy. There is a need felt for pharmacogenomics studies, where the effects of multiple genes are assessed with the study of entire genome [8].

Nonclinical safety data are used to select doses in Phase I clinical trial, to provide information on potential side eff...