The Nonhuman Primate in Nonclinical Drug Development and Safety Assessment

Joerg Bluemel, Sven Korte, Emanuel Schenck, Gerhard Weinbauer

• Publisher: Academic Press
• Year: 2015
• Print ISBN: 9780124171442
• eBook ISBN: 9780124171466
• Topic: Medicine
• Subtopic: Pharmacology

The Nonhuman Primate in Drug Development and Safety Assessment is a valuable reference dedicated to compiling the latest research on nonhuman primate models in nonclinical safety assessment, regulatory toxicity testing and translational science. By covering important topics such as study planning and conduct, inter-species genetic drift, pathophysiology, animal welfare legislation, safety assessment of biologics and small molecules, immunotoxicology and much more, this book provides scientific and technical insights to help you safely and successfully use nonhuman primates in pharmaceutical toxicity testing. A comprehensive yet practical guide, this book is intended for new researchers or practicing toxicologists, toxicologic pathologists and pharmaceutical scientists working with nonhuman primates, as well as graduate students preparing for careers in this area.- Covers important topics such as species selection, study design, experimental methodologies, animal welfare and the 3Rs (Replace, Refine and Reduce), social housing, regulatory guidelines, comparative physiology, reproductive biology, genetic polymorphisms and more- Includes practical examples on techniques and methods to guide your daily practice- Offers a companion website with high-quality color illustrations, reference values for safety assessment and additional practical information such as study design considerations, techniques and procedures and dosing and sampling volumes

VIII

Special Toxicity Testing with Nonhuman Primates

Chapter 25

Developmental and Reproductive Toxicity Testing

Gerhard F. Weinbauer*; Christopher J. Bowman^†; Wendy G. Halpern^‡; Gary J. Chellman^{§ *} Covance Laboratories GmbH, Münster, Germany
^† Pfizer Inc, Groton, CT, USA
^‡ Genentech, South San Francisco, CA, USA
^§ Charles River Laboratories, Reno, NV, USA

Abstract

Nonhuman primates (NHPs) are an important model for evaluating the potential effects of new biopharmaceuticals on male and female reproduction and pre- and postnatal development. Toxicity testing for these parameters should be conducted in NHPs only when they are the only relevant species or are critical for the human risk assessment. In general, evaluation of potential effects on male and female reproduction can be included in general toxicity studies using sexually mature animals, and effects on development can be assessed in a single, well-designed developmental toxicity study. In the case of specific concerns about effects on the reproductive system, additional studies may be considered. Although the concepts of standard toxicity testing for development and reproduction still apply, the NHP model requires different considerations and in most cases must be tailored based on the type of molecule, the intended patient population, and the expected pharmacology to enable the optimal use of these animals.

Keywords

Nonhuman primate

Placenta

Cynomolgus

Marmoset

Rhesus

ePPND

Embryo-fetal

Postnatal

ICH

Abortion

Outline

Introduction 472

Which NHP Model? 473

Fertility and Early Embryonic Development Study 474

Study Design Options 475

Sexual Maturity Determination 478

Embryo-Fetal Development 479

Study Design Options 479

Prenatal and Postnatal Development 482

Study Design Options 482

Group Size and “3 R” Considerations 486

Reproductive Toxicity Studies 487

Implications of Social Housing for Evaluation of the Reproductive System 488

Developmental Toxicity Studies 490

Relevance of ADAs 491

Placenta: Target Organ and Transport 491

Data Interpretation Challenges Associated with Background Changes in Pregnant NHPs 493

Conclusion 493

References 496

Introduction

Developmental and reproductive toxicity (DART) testing is commonly done using rodents (mice or rats) and rabbits. Nonhuman primate (NHP) models are needed for DART testing when they are the only pharmacologically relevant species or offer critical features not found in other species. For biopharmaceuticals with highly targeted activity, pharmacological relevance is a requirement (ICH S6(R1)) [1]. DART evaluations generally use standardized experimental designs, described in detail in the ICH S5(R2) guideline [2], and comprised of three study types:

• Fertility and early embryonic development (4.1.1)

• Prenatal and postnatal development (PPND) (4.1.2)

• Embryo-fetal development (EFD) (4.1.3)

The segmented approach for DART testing is still in place for pharmaceuticals, whereas this approach has undergone substantial modification for biopharmaceuticals if NHPs are the only relevant species. In that case, a specific EFD study can be omitted, as per ICH M3(R2) [3] and ICH S6(R1), since the placental transfer of large molecules is assumed to be low during first trimester (organogenesis) and evaluation of potential external, visceral, and skeletal developmental abnormalities can be incorporated into the design of the PPND study as a postnatal assessment; this integrated design is known as an enhanced PPND (ePPND) study [4,5] and is described in detail in ICH S6(R1). ICH S6(R1) also acknowledges that functional fertility studies using NHPs are not routine if the NHP is the only pharmacologically relevant species and that reproductive parameters incorporated into chronic repeat-dose toxicity studies using sexually mature animals are appropriate in most instances.

The concept of species selection in general and in the specific context of DART evaluation have been the subject of comprehensive reviews [6,7] and are described in Chaps. 16,34 in this book. Biopharmaceutical development frequently requires the use of NHP models, necessitated by the species specificity of the test article properties [8–12]. Importantly, species selection should be based on the pharmacological relevance of the chosen species rather than a default approach (ICH S6(R1)), and it is not uncommon that NHPs represent the only relevant animal model. As a consequence of more biopharmaceuticals being developed, conducting DART studies using the NHP model is now more common, and NHPs are recognized as an important model for DART evaluation of monoclonal antibodies (mAbs) [13]. For example, in a review of the European Medicines Agency database through 2010, NHPs were used for 23 of 30 mAbs evaluated preclinically in DART studies [14].

In addition to species considerations dictated by test article-specific properties, NHPs generally offer several advantages over rodents and rabbits with regard to DART because of similarity to humans, for example, the endocrinology of testicular and ovarian function, the endocrinology of early pregnancy, placental morphology and physiology, timing of implantation and rates of embryonic development, and similar responses to known human teratogens such as thalidomide, valproic acid, and vitamin A [15,16]. On the other hand, the use of NHPs poses ethical and practical limitations. Default litter size of macaques is 1 compared with 12 and 6 in rodents and rabbits, respectively. Fertility rates in macaques are low (typically around 60% per animal), and preimplantation loss in macaques is high. Therefore, ultrasound-confirmed pregnancy is the preferred approach before starting a developmental toxicity study, with dosing rarely initiated before gestational day (GD) 20 in macaques. However, implantation occurs at approximately GD 9-10, and therefore the period immediately following implantation is not typically evaluated as it is in rodents and rabbits. Also, study durations of NHP EFD studies overall are three to five times longer than rodent or rabbit EFD studies and are associated with a commensurately high cost factor. For practical reasons, group sizes and number of offspring evaluated in NHP DART studies are substantially smaller compared with rodent/rabbit models [9].

Another point to note is that pregnant NHPs are not available from commercial breeders, so a mating program needs to be in place at the test site. Hence, several weeks to months may be required until all animals are enrolled in the study. Timed matings are achieved by vaginal swab-based monitoring of the ovarian cycle and pairing around the suspected time of ovulation followed by ultrasound examination for pregnancy. Since ovarian cycles cannot be synchronized [17,18], every female animal—once pregnant—is on its own timeline during the remainder of the study, and this adds significant complexity compared to a chronic study (see Figure 25.1 for details).

Figure 25.1 Graphic representation of the complexity of a nonhuman primate (NHP) developmental toxicity study, exemplified by an enhanced pre- and postnatal development (ePPND) toxicity study, compared with a chronic NHP toxicity study. “Planned” indicates the number of activities based on the study plan, and “empirical” denotes the actual numbers of activities encountered. Because pregnant NHPs are not commercially available, animals must be mated on site to generate pregnant NHPs. Hence, the study plan-based day-by-day activities in a developmental toxicity study depend on the accrual rate of pregnant animals. Empirical versus planned means the number of day-based activities according to the study plan (all animals pregnant) versus the actual entry of pregnant animals into study. In a chronic toxicity study, planned typically matc...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• I: Genetics of Nonhuman Primate Species Commonly Used in Drug Development
• II: Comparative Physiology of Nonhuman Primate Species Used in Nonclinical Safety Assessment and Drug Development
• III: Pathophysiology of Nonhuman Primate Species Used in Nonclinical Safety Assessment and Drug Development
• IV: The 3 Rs and Animal Welfare
• V: The Role of Nonhuman Primates in Safety Assessment/regulatory Toxicology
• VI: Translational Aspects for the Use of Nonhuman Primates in Drug Development
• VII: Nonhuman Primate-specific Aspects of Standard Toxicology Studies
• VIII: Special Toxicity Testing with Nonhuman Primates
• IX: Future Trends in Primate Toxicology
• Index