Electrocardiography of Laboratory Animals

Jeffrey W. Richig, Meg M. Sleeper

• Publisher: Academic Press
• Year: 2018
• eBook ISBN: 9780128097007
• Edition: 2
• Topic: Ciencias biológicas
• Subtopic: Biología

Electrocardiography of Laboratory Animals, Second Edition, is the only publication covering electrocardiography of laboratory animals. With countries instituting requirements for the care of laboratory animals in research, this publication offers a standard on performing and analyzing ECGs. Topics covered include safety electrocardiography, toxicology, safety pharmacology, and telemetry, all important areas of discussion for biological and medical researchers, veterinarians, zoologists, and students who need to understand the electrocardiography of five species of animals used in research: canines, nonhuman primates, mini pigs, rodents (rats and mice), rabbits and cats.- Offers guidance in interpretation of laboratory animal ECGs by animal type- Provides comparisons of ECGs across animal species- Includes coverage of three animal species: canines, nonhuman primates and mini pigs, also including three additional species: rodents (rats and mice), rabbits and cats- Supports adherence to FDA requirements of ECG performance and qualitative analysis on large laboratory animals

Chapter 1

Electrocardiography in Preclinical Safety

Abstract

This chapter covers general aspects of safety pharmacology and toxicology, and the significant role that the electrocardiogram plays in drug safety evaluation. The chapter also covers examples of study design for both safety pharmacology and toxicology studies, and how the electrocardiogram can be incorporated in those studies.

Keywords

Electrocardiogram (ECG) and study design; Good Laboratory Practice (GLP); International Conference on Harmonization (ICH); Safety pharmacology; Toxicology

Introduction

Electrocardiography has become increasingly important in preclinical safety studies in light of the fact that certain drugs have been pulled from the market due to adverse cardiac findings. From the preclinical perspective, the reliance on postmortem data in animal safety studies to identify target organs of toxicity unfortunately leaves large gaps in the ability to noninvasively monitor organ function and/or integrity; therefore the use of electrophysiological tools for tissues, such as the heart, provides data that in many cases are directly correlatable to that generated from human trials.

Given the potential for cataclysmic fallout from drug or chemical-induced alterations in the electrocardiogram (ECG), ECG data is considered vital information in characterizing potential drug or chemical-induced cardiac toxicities, and are typically an essential part of study protocols involving dogs, monkeys, or minipigs in support of human safety. Although many drugs have pharmacologic actions that impact cardiac function at high doses, the margin of safety under a drug's expected or intended use distinguish a potential adverse reaction from an effect precluding a drug's further clinical development or marketability. Hence, the rationale is clear for evaluating the electrocardiogram in animal studies under very close scrutiny at single doses as expected in initial human trials, and under repeat-dose conditions, as might be expected with more chronic treatment.

In preclinical drug development, animal studies are conducted to determine what possible target organs of toxicity might be expected if the drug candidate were to be further developed in humans, and

1. • How those effects might preclude the possibility of safely proceeding into clinical trials?
2. • How the potential adverse effects might be monitored in humans?

It oftentimes rests on whether a potential serious adverse effect noted in animal studies may be monitored in humans with adequate safety margins in place and the likelihood of reversibility.

Alterations in the electrocardiogram are considered a very serious adverse effect; however, since this change is clinically monitorable and typically a reversible phenomenon, drug candidates impacting the electrocardiogram in animal studies are not necessarily precluded from further development. On the other hand, those agents that produce serious adverse changes with no monitorable clinical correlate (e.g., histological evidence of neuronal damage) and/or little evidence of recovery are generally considered too risky for most types of clinical indications to devote resources for further development. Exceptions to this rule include adverse changes produced from chronic drug exposure in animals that have little or no relevance to humans (e.g., certain drug-induced thyroid adenomas and other tumors in rodents with no mechanistic relevance to humans).

Regulatory Guidance Versus Good Science Versus Rationale Drug Development

What to Do When?

Most large pharmaceutical companies have a keen awareness of the valuable time and expense required to go back and “fill in the boxes” for product registration, or of the risk of insufficient toxicology in their Investigational New Drug (IND) package; therefore there is a great amount of attention paid up front to regulatory requirements. Smaller companies with more critical funding or timing issues generally equate box-checking with time delays, and therefore question what is really required versus what is needed to ensure safety and to assure that their drug does not meet with funding-fatal resistance from regulators at any step toward their major milestones.

In fact, for the preclinical portion of a drug's development lifespan, there is very little that is actually required in terms of specific testing regimens in animals prior to safely proceeding into humans; however, numerous regulatory guidance documents provide key insight into the minimum that drug regulatory agencies are expecting to see in support of human safety.

An international regulatory steering committee, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), in the past several years has been instrumental in giving investigators a window into the commonality of thinking as well as the differences in approach of regulatory agencies representing the United States, the European Union, and Japan.

Fortunately, the ICH has spent a great amount of time and focus on defining the approach a company should take in assessing cardiovascular safety prior to “first in man” studies, and has drafted guidelines to assist investigators in this area. These guidelines have focused on the types and nature of safety pharmacology studies (single-dose studies typically at pharmacologically relevant doses) and attempt to give investigators a roadmap for what to do at various stages of preclinical drug development. Of course, these types of guidance documents by design still leave ample room for interpretation and in fact, one size never really does fit all. The term “good science” is also often used in attempting to guide decision-making and establishing a workable flowchart of decision points for toxicity testing of potential new drugs, especially early on in their discovery or development journeys.

Unfortunately, good science is just that, and does not take into account the potential use of the drug; the relative risk versus potential benefit; and how to weigh the factors influencing target-organ toxicity (in this case, cardiotoxicity), dose, mechanism, interspecies metabolism, target patient population, and conditions of use, for example, with a go/no-go decision mentality so vital for optimal use of a drug company's resources. I would like to think that regulatory requirements and guidelines are a given, as well as the use of good science throughout the process, but the term rational drug development should be thought of as the approach to take with each potential new therapeutic entity.

Drugs that target the elderly, or are intended for those patients who are also likely to have impaired cardiovascular function (e.g., Alzheimer drugs, antidiabetic agents, or drugs likely to be used in combination with cardiotoxic chemotherapeutic agents, antihistamines, or antimicrobials) should also be considered for some form of early cardiotoxicity screening.

The cardiotoxic screening approach should be well-customized to answer the specific question at hand, but in general, we should consider in vitro (e.g., hERG [human ether-a-go-go-related gene] assay and Purkinje fibers), ex vivo (e.g., isolated papillary muscle and atria), and/or in vivo (e.g., small-scale nonrodent acute or short-term repeat-dose cardiovascular study) screening studies early in the process.

There is clearly no right or wrong way to approach this, no single assay or test system, but the screen should match the reason for doing the test.

For example, drugs with structural alerts for interfering with cardiac repolarization conduction pathways might first be tested in a hERG assay, but this approach would not be appropriate for agents expecting to affect estrogen levels through secondary mechanisms. In the latter case, a short-term (e.g., 2-week) pilot nonrodent cardiotoxicity study at fairly robust multiples of the projected human dose might be a more appropriate screen. In some cases, investigators may need to look at several types of screens for profiling a new drug's potential for impacting cardiovascular safety.

Even with all the data in hand, it is often not clear whether to invest more resources in further development of the compound or bring its current development plan to a grinding halt. These decisions at times may become more emotional or political than rational, but they do not have to be. At this point, advice, such as “stop and think” or “evaluate,” may save a company from discarding a drug prematurely, or continuing when they probably should not. Factors to consider at this stage are risk/benefit, availability of alternative therapies, the value of additional mechanistic or pilot animal studies, potential adverse drug interactions, am...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Acknowledgments
• Chapter 1. Electrocardiography in Preclinical Safety
• Chapter 2. Fundamental Principles of Electrocardiography
• Chapter 3. Electrocardiography of Rodents
• Chapter 4. Electrocardiography of Rabbits
• Chapter 5. Feline Electrocardiography
• Chapter 6. Canine Electrocardiography
• Chapter 7. Handling and Restraint of Nonhuman Primates
• Chapter 8. Electrocardiography of Nonhuman Primates
• Chapter 9. Electrocardiography of Neonates/Juveniles
• Chapter 10. Electrocardiography of Minipigs
• Chapter 11. Telemetry in Preclinical Safety Studies
• Chapter 12. PR (PQ), QRS, QT, and Other Issues
• Chapter 13. Blood Pressure
• Chapter 14. Self-Assessment
• References
• Index