Advances in Delivery Science and Technology
`
`Series Editor
`Michael J. Rathbone
`
`For further volumes:
`http://www.springer.com/series/8875
`
`Medac Exhibit 2004
`Koios v. Medac
`IPR2016-01370
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` Michael J. Rathbone  Arlene McDowell
` Editors
`
` Long Acting Animal Health
`Drug Products
`
` Fundamentals and Applications
`
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`

` Editors
` Michael J. Rathbone
` Division of Pharmacy
` International Medical University
` Bukit Jalil, Kuala Lumpur , Malaysia
`
` Arlene McDowell
` New Zealand’s National School of Pharmacy
` University of Otago
` Dunedin , New Zealand
`
` ISSN 2192-6204
`
`
`
`ISBN 978-1-4614-4438-1
` DOI 10.1007/978-1-4614-4439-8
` Springer New York Heidelberg Dordrecht London
`
`ISSN 2192-6212 (electronic)
` ISBN 978-1-4614-4439-8 (eBook)
`
` Library of Congress Control Number: 2012948612
`
` © Controlled Release Society 2013
` This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
`the material is concerned, speci fi cally the rights of translation, reprinting, reuse of illustrations, recitation,
`broadcasting, reproduction on micro fi lms or in any other physical way, and transmission or information
`storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
`now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection
`with reviews or scholarly analysis or material supplied speci fi cally for the purpose of being entered and
`executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this
`publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s
`location, in its current version, and permission for use must always be obtained from Springer. Permissions
`for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to
`prosecution under the respective Copyright Law.
` The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
`does not imply, even in the absence of a speci fi c statement, that such names are exempt from the relevant
`protective laws and regulations and therefore free for general use.
` While the advice and information in this book are believed to be true and accurate at the date of publication,
`neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or
`omissions that may be made. The publisher makes no warranty, express or implied, with respect to the
`material contained herein.
`
` Printed on acid-free paper
`
` Springer is part of Springer Science+Business Media (www.springer.com)
`
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` This book is dedicated to my father
`George Frederick Rathbone who recently
`passed away… the man who gave me
`the wisest of my education
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` Preface
`
` Long-acting veterinary formulations play a signi fi cant role in animal health,
`production, and reproduction within the animal health industry. Such technologies
`offer bene fi cial advantages to the veterinarian, farmer, and pet owner. These advan-
`tages have resulted in long-acting formulations growing in popularity in recent years.
` The pharmaceutical scientist is faced with many challenges when innovating
`new products in this demanding fi eld of controlled release. This volume provides
`the reader with a comprehensive guide on the theories, applications, and challenges
`associated with the design and development of long-acting veterinary formulations.
`The authoritative chapters of the book are written by some of the leading experts in
`the fi eld. It covers a wide scope of areas including the market in fl uences, preformu-
`lation, biopharmaceutics, in vitro drug release testing, and speci fi cation setting to
`name a few. It also provides a detailed overview of the major technological advances
`made in this area. As a result, Long Acting Animal Health Drug Products covers
`everything a formulation scientist in industry or academia or a student needs to
`know about this unique drug delivery fi eld to advance health, production and repro-
`duction treatment options, and bene fi ts for animals worldwide.
` In chapter 1 Sabnis and Rathbone de fi ne the current animal health markets for
`farmed animals and evaluate the opportunities that exist. The chapter provides an
`outlook for future projections of growth in the livestock industry and the likely
`resultant demands of the farmed animal health market. In the second chapter Linda
`Hoorspool conducts a similar analysis (with quite different conclusions) for the
`companion animal market.
` The anatomy and physiology of the farmed and companion animals are provided
`by Ellis and Sutton, respectively. These chapters describe the large differences
`between ruminant (cattle and sheep) and monogastric animals (speci fi cally cats and
`dogs) and highlight the different challenges (and opportunities) faced by formula-
`tion scientists in designing and developing long-acting veterinary products for these
`two physiologically and anatomically different types of animals.
` Chapter 5 provides a comprehensive overview of the physicochemical principles
`of controlled release veterinary pharmaceuticals. In this contribution Fletcher et al.
`describe the basic physical and chemical properties relevant to drug formulation
`
`vii
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`viii
`
`Preface
`
`which includes the active pharmaceutical ingredient, excipients, and fi nal product.
`The chapter also highlights the importance of physical and chemical attributes of
`compounds in the selection of ingredients; development of dosage forms; and their
`signi fi cance with respect to active and fi nal product assessment, characterization, per-
`formance, and quality. Sutton describes the basics of biopharmaceutics and its rele-
`vance in veterinary drug delivery. This chapter discusses studies that emphasize the
`similarities and differences in species and routes of administration. From nasal and
`ocular to transdermal and oral, examples of formulations for veterinary practice are
`discussed. The main concepts related to analytical testing of veterinary drug products
`and the development of speci fi cations for critical quality attributes are addressed by
`Brum fi eld. This excellent and comprehensive chapter will be of value to anyone
`working in the industrial setting. Brum fi eld describes pragmatic strategies for the
`development and use of analytical speci fi cations throughout the veterinary product
`development and commercialization life cycle. Also presented are typical analytical
`testing requirements for quality assessment and registration of selected types of prod-
`ucts in major markets (USA, EU, and Japan), and unique challenges related to several
`veterinary-centric dosage forms including medicated articles for preparation of feeds
`and drinking waters, and topical parasiticide preparations. The challenges of develop-
`ing and undertaking in vitro drug release testing of veterinary pharmaceuticals are
`described in the following chapter by Higgins-Gruber. Long-acting veterinary dosage
`forms tend to be more complex and varied because of the diversity of species and size
`of the animals. Therefore, the development of in vitro drug release tests for such prod-
`ucts can be challenging and unconventional with respect to the expectations from the
`regulatory agencies. Higgins-Gruber describes the principles taken into consideration
`when developing an in vitro drug release test for long-acting veterinary pharmaceuti-
`cals that is easy to perform in a quality control environment whilst being discriminat-
`ing with respect to the impact of critical quality attributes on in vivo behavior.
` The remaining contributions of the book describe technological advances in the
` fi eld of long-acting veterinary products. Chapters devoted to long-acting rumen drug
`delivery systems (Vandamme), intravaginal veterinary drug delivery (Rathbone),
`long-acting injections and implants (Cady), intramammary delivery technologies
`(Alany), veterinary vaccines (Elhay), and delivery systems for wildlife (McDowell) all
`provide a wealth of information and insight into the current strategies and contemporary
`research adopted in the development of long-acting veterinary drug delivery systems.
` In the fi nal chapter of the book Baird examines the emerging drug discovery
`technologies in both the human and animal drug delivery fi elds and discusses the
`potential for cross over of the learnings, technologies, and outcomes from these
`areas that result in “spin off” bene fi ts for veterinary medicine. The chapter makes
`for some interesting reading.
` We thank all the authors for their time and effort to put pen to paper to share their
`experiences and knowledge in this volume. Without their interest and commitment
`to the area of long-acting animal health products this book would not be the treasury
`of knowledge that it is.
`
`Kuala Lumpur, Malaysia
`Dunedin, New Zealand
`
`Michael J. Rathbone
`Arlene McDowell
`
`Page 00008
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`

`Contents
`
`
`
` 1 Animal Health Markets and Opportunities:
`Farmed Animal Landscape ...................................................................
`Shobhan Sabnis and Michael J. Rathbone
`
` 2 Animal Health Markets and Opportunities:
`Companion Animal Landscape .............................................................
`Linda J.I. Horspool
`
` 3 Anatomy and Physiology of the Farmed Animal ................................
`Keith J. Ellis
`
` 4 Oral Anatomy and Physiology in the Companion Animal .................
`Steven C. Sutton
`
` 5 Physicochemical Principles of Controlled Release
`Veterinary Pharmaceuticals ..................................................................
`John G. Fletcher, Michael J. Rathbone, and Raid G. Alany
`
` 6 Biopharmaceutics and Veterinary Drug Delivery ...............................
`Steven C. Sutton
`
`1
`
`15
`
`47
`
`59
`
`69
`
`97
`
` 7 Quality by Design and the Development of Solid
`Oral Dosage Forms ................................................................................ 107
`Raafat Fahmy, Douglas Danielson, and Marilyn N. Martinez
`
` 8 Final Product Testing and the Development
`of Specifications for Veterinary Pharmaceuticals ............................... 131
`Jay C. Brumfield
`
` 9 In Vitro Drug Release Testing of Veterinary Pharmaceuticals .......... 193
`Shannon Higgins-Gruber, Michael J. Rathbone,
`and Jay C. Brumfield
`
`10 Long Acting Rumen Drug Delivery Systems ....................................... 221
`Thierry F. Vandamme and Michael J. Rathbone
`
`ix
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`

`x
`
`Contents
`
`11 Controlled Release Intravaginal Veterinary Drug Delivery .............. 247
`Michael J. Rathbone and Christopher R. Burke
`
`12 Veterinary Long-Acting Injections and Implants ............................... 271
`Susan M. Cady, Peter M. Cheifetz, and Izabela Galeska
`
`13 Intramammary Delivery Technologies for Cattle
`Mastitis Treatment ................................................................................. 295
`Raid G. Alany, Sushila Bhattarai, Sandhya Pranatharthiharan,
`and Padma V. Devarajan
`
`14 Veterinary Vaccines ................................................................................ 329
`Martin J. Elhay
`
`15 Delivery Systems for Wildlife ................................................................ 345
`Arlene McDowell
`
`16 Human: Veterinary Technology Cross Over ....................................... 359
`Alan W. Baird, Michael J. Rathbone, and David J. Brayden
`
`About the Authors .......................................................................................... 377
`
`Index ................................................................................................................ 379
`
`Page 00010
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`

`

` Contributors
`
` Raid G. Alany School of Pharmacy and Chemistry, Kingston University , Kingston
`upon Thames , UK
` Alan W. Baird UCD School of Veterinary Medicine, University College Dublin ,
` Bel fi eld , Ireland
` Sushila Bhattarai Bomac Laboratories Limited , Bayer Animal Health New
`Zealand , Auckland , New Zealand
` David J. Brayden UCD School of Veterinary Medicine, University College Dublin ,
` Bel fi eld , Ireland
` Jay C. Brum fi eld Merck Animal Health , Summit , NJ , USA
` Christopher R. Burke DairyNZ , Hamilton , New Zealand
` Susan M. Cady Merial Limited (A Sano fi Company) , North Brunswick , NJ , USA
` Peter M. Cheifetz Merial Limited (A Sano fi Company) , North Brunswick , NJ , USA
` Douglas Danielson Perrigo Company , Allegan , MI , USA
` Padma V. Devarajan Department of Pharmaceutical Sciences and Technology ,
` Institute of Chemical Technology , Mumbai , India
` Martin J. Elhay Veterinary Medicines R&D, P fi zer Animal Health , Parkville,
`VIC , Australia
` Keith J. Ellis Ellis Consulting , Armidale, NSW , Australia
` Raafat Fahmy Center for Veterinary Medicine, Office of New Drug Evaluation,
`Food and Drug Evaluation, Food and Drug Administration , Rockville , MD , USA
` John G. Fletcher School of Pharmacy and Chemistry, Kingston University ,
` Kingston upon Thames , UK
`
`xi
`
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`
`

`

`xii
`
`Contributors
`
` Izabela Galeska Merial Limited (A Sano fi Company) , North Brunswick , NJ ,
` USA
` Shannon Higgins-Gruber Merck Animal Health , Summit , NJ , USA
` Linda J.I. Horspool MSD Animal Health, Boxmeer , The Netherlands
` Marilyn N. Martinez Center for Veterinary Medicine, Office of New Drug
`Evaluation, Food and Drug Evaluation, Food and Drug Administration , Rockville ,
` MD , USA
` Arlene McDowell New Zealand’s National School of Pharmacy, University of
`Otago , Dunedin , New Zealand
` Pranatharthiharan Department of Pharmaceutical Sciences and
` Sandhya
`Technology , Institute of Chemical Technology , Mumbai , India
` Michael J. Rathbone Division of Pharmacy , International Medical University ,
` Kuala Lumpur , Malaysia
` Shobhan Sabnis Global Manufacturing Services, P fi zer Animal Health , Greater
`New York City Area , USA
` Steven C. Sutton College of Pharmacy, University of New England , Portland , ME ,
` USA
` Thierry F. Vandamme Faculté de Pharmacie, Laboratoire de Conception et
`d’Application des Molécules Bioactives , Université de Strasbourg , Illkirch Cedex ,
` France
`
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`

`

` Chapter 16
` Human: Veterinary Technology Cross Over
`
` Alan W. Baird , Michael J. Rathbone , and David J. Brayden
`
` Abstract Emerging drug discovery technologies are helping us to break from the
`traditional simplistic cycle of animal experimentation for human applications with
`“spin off” bene fi ts for veterinary medicine. A more coordinated effort can develop
`synergies. In this chapter we attempt to pro fi le how those technologies harnessed
`independently for human or veterinary medicine have related features. We discuss
`shared approaches and requirements that are reaping bene fi ts for both human and
`veterinary patients.
`
` 16.1
`
` Introduction
`
` “ Every advance made in human medicine affects the progress of veterinary sci-
`ence… .” [Encyclopaedia Britannica Eleventh Edition (1910–1911)] and perhaps the
`converse is equally true. From traditional beginnings, therapeutic and diagnostic
`practices have bene fi tted from developments in basic sciences through physics,
`chemistry, biology, mathematics, and increasingly through computer power. One
`hundred years after the statement was published, we are fortunate enough to be in a
`period when the revolutions in molecular technology and mathematical modeling
`are colliding in an exciting manner. Researchers today have access to techniques
`beyond the imagination of their counterparts 10 years ago. In this chapter we explore
`how human and veterinary science as well as clinical practice are sharing techno-
`logical progress.
`
` A. W. Baird • D. J. Brayden (*)
` UCD School of Veterinary Medicine, University College Dublin , Bel fi eld , Dublin 4 , Ireland
`e-mail: david.brayden@ucd.ie
`
` M. J. Rathbone
` International Medical University , Kuala Lumpur , Malaysia
`
`M.J. Rathbone and A. McDowell (eds.), Long Acting Animal Health Drug Products:
`Fundamentals and Applications, Advances in Delivery Science and Technology,
`DOI 10.1007/978-1-4614-4439-8_16, © Controlled Release Society 2013
`
`359
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`360
`
`A.W. Baird et al.
`
` The previous chapters of this book explore comparative aspects of drug delivery
`related to animal health. Although fundamental principles of anatomy, physiology,
`and biochemistry govern pharmacokinetic (PK) pro fi les of all species, complexity
`in how certain drugs are orally absorbed, protein bound, metabolized, and elimi-
`nated via transporters in different species means that reliance on allometric scaling
`to predict dosing requirements between species is usually erroneous. Optimized
`clinical trial design to pro fi le PK even in the same species has yet to be achieved as
`data is not normally required by regulatory authorities in the pediatric, geriatric or
`the sick patient, even though clearance may differ in each. Still, the concept that
`man represents just one other species is justi fi ably promoted throughout this collec-
`tion. Science is in the early stages of understanding how genetic differences within,
`as well as between, species can affect the way drugs work. The genomes of rodents
`are turning out to be remarkably similar to humans. In many cases, even genetic
`linkages have been conserved. As such new information and understanding accu-
`mulates, maintained by the relatively new discipline of bio-informatics, genetically
`de fi ned animal models become increasingly valuable in gaining an understanding of
`human disease. Pharmacogenomics offers as many opportunities in rational drug
`discovery in veterinary medicine as it does in human medicine in order to tailor
`molecules to have improved safety and ef fi cacy in strati fi ed populations within and
`between species. Recent technical developments including sequencing of the
`genomes of a range of species and the development of molecular techniques are
`sometimes referred to as “omics.” Such powerful approaches have encouraged
`developments in data management, computation and analysis, leading to the “new”
`science of Systems Biology.
`
` 16.2
`
` Biomarkers
`
` The term biomarker is one that is used differently in different settings. Some impor-
`tant accepted biomarkers are based on sensitive chemical detection of speci fi c
` analytes in biological fl uids [ 1 ] . Such technology is applicable in both human and
`animal domains. For example, chemical detection of xenobiotics [ 2 ] ranges from
`biosurveillance of pollutants in the environment, through forensic applications,
`including doping of athletes (humans, greyhounds, or horses) to therapeutic drug
`monitoring for agents with a low therapeutic index. Military applications of
` biomarkers have also been described [ 3 ] as well as their applications in space medi-
`cine [ 4 ] . Other examples include biomarkers to identify illegal growth promoters in
`beef cattle [ 5 ] and to detect contaminants in food [ 6 ] . Diagnostic parameters (heart
`rate, blood pressure, growth rate, blood biochemistry) are biomarkers that are
`homeostatically maintained with normal ranges, and are therefore useful indicators
`of health or of pathological changes. Similarly, biomarkers may be used to indicate
`whether xenobiotics administered to an animal may affect functional parameters
`and, in the case of therapeutics, can indicate whether normal function is being
`restored.
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`

`16 Human: Veterinary Technology Cross Over
`
`361
`
` It is now possible to detect low-abundance receptor targets including speci fi c
`sequences of nucleic acids and proteins as well as aspects of post-translational
`modi fi cation in complex mixtures using microarrays: capture, reverse-phase, tissue,
`lectin, and cell-free expression [ 7 ] . These technologies, many of which are
` commercially available and used in clinical diagnoses, also have research value in
`proteomics studies including future biomarker discovery, protein interaction stud-
`ies, enzyme-substrate pro fi ling, immunological pro fi ling, and vaccine development.
`The need to detect extremely low-abundance proteins in complex mixtures has
` provided motivation for the development of sensitive, real-time, and multiplexed
`detection platforms. Recently, biomarkers for some human diseases have emerged,
`including prostate speci fi c antigen (PSA) for prostate cancer [ 8 ] , C-reactive protein
`(CRP) for heart disease [ 2 ] , and an inverse correlation between plasma glycosylated
`hemoglobin (HbA (1c)) and Type II diabetes [ 9 ] . Using biomarkers from blood or
`urine offers surrogate measures of pathology affecting poorly accessible tissues or
`organs or even cells in solid tumors [ 10 ] . Biomarkers are also essential in develop-
`ing toxicology methodology by enhancing the speci fi city and sensitivity of predic-
`tion assays. One consequence such an approach has had is to reduce the numbers of
`animals used in toxicity testing [ 11 ] .
` Sophistication in biomarker discovery has been extended through “omics” tech-
`niques [ 12– 15 ] to identify relevant markers rapidly. Biomarker discovery tools
`include transcriptomics (the study of RNA transcript expression), metabolomics
`(the study of metabolite expression), and proteomics (the study of protein expres-
`sion patterns) [ 16, 17 ] . Currently, a validated biomarker may be used in high
`throughput screening in human or in veterinary pathology, drug discovery, and in
`safety assessments [ 18 ] . Identi fi cation of clinically important protein and genetic
`biomarkers of phenotype and of speci fi c biological function is an expanding area of
`research that will extend diagnostic capabilities [ 19 ] . Biomarkers also provide use-
`ful information related to vaccine design and delivery [ 19 ] . With respect to preven-
`tive vaccines, biomarkers, for example in responses to BCG challenge [ 20 ] , have
`potential to predict outcome and/or to predict effectiveness. In the case of therapeu-
`tic vaccines, biomarkers may be used to predict subject immune response and safety,
`re fl ected by genetic features of the host that relate to quality and type of immunity
`generated.
` Biomarkers have traditionally provided information regarding diagnosis, prog-
`nosis, and treatment of genetic disorders, as well as for indications of therapeutic
`ef fi cacy in treating infectious and non-infectious diseases across species.
`Bioinformatics methods have empowered this approach greatly by pro fi ling bio-
`marker patterns in clinical metabolomics, using chemical fi ngerprints that biologi-
`cal processes produce. Data mining tools are used to interrogate data gathered from
`complicated studies informing future clinical applications [ 21 ] .
` In addition to sequence information (of DNA, RNA, and proteins), epigenetics is
`also beginning to provide methods with which to identify biomarkers of health and
`disease. For example, histone modi fi cation [ 22, 23 ] or altered DNA methylation
`patterns showing up in genome-wide association studies (GWASs) may have future
`applications in identifying loci associated with common diseases [ 24 ] . Perhaps the
`
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`

`362
`
`A.W. Baird et al.
`
`presence of hand-held PCR machines [ 25 ] in every clinic, of fi ce, or even farm is not
`too far off.
` Before concluding this section on biomarkers, it is worth remembering that ani-
`mals, or populations of animals, have been used throughout history as de facto sur-
`rogate predictive biomarkers for human toxicity. Examples range from canaries
`used in coal-mines as indicators of methane gas contamination to environmental
`sentinels of environmental hazards (e.g., trout sensitivity to cadmium toxicity in
`fresh water) [ 26, 27 ] .
`
` 16.3
`
` Drugs for Human Use Developed in Animals
`
` Traditional drug discovery has employed whole animals and animal tissues for
`in vivo and in vitro drug research [ 28, 29 ] . Thus, animals have always contributed
`to research leading to market authorization of new medicines for man. Animal mod-
`els of human diseases [ 30– 32 ] have been useful in basic and applied research,
`although their relevance at the level of accurate pathology and toxicology as well as
`for predictive therapeutic ef fi cacy in man tends to be disease-dependent [ 33, 34 ] .
`One historic example, often cited, is the discovery of insulin’s role in human Type 1
`diabetes using dogs [ 35 ] , which unveiled the eventual role for porcine insulin in
`replacement therapy. For many decades, animal sources of insulin were used in
`humans, with drawbacks, including immunological sensitization as well as the pos-
`sibility of contaminated sources, many of which have been overcome following the
`development of recombinant humanized insulin [ 36, 37 ] . Ironically, therapeutic
`bene fi ts of new drug entities which were originally developed for human use using
`animal models of disease and toxicology may return to a veterinary setting when an
`established marketed human drug is leveraged for veterinary applications. An
`example is Clomicalm® (clomipramine hydrochloride) (Novartis Animal Health,
`Basel, Switzerland), a reformulated human tricyclic antidepressant, now approved
`to treat separation anxiety in dogs [ 38 ] . For many human conditions or diseases
`including cancers, stroke, and Alzheimer’s disease, there are no really useful animal
`models [ 39– 43 ] and this has delayed therapeutic advances. Less known is that other
`animal models have been highly successful and have led to predictive therapeutic
`outcomes in man, an example being rodent experimental autoimmune encephalo-
`myelitis (EAE), which was instrumental in development of the fi rst antibody ther-
`apy to a 4 integrin for multiple sclerosis patients [ 44 ] . There is now considerable
`interest from human clinicians in using canine clinical cases that display spontane-
`ous cancers for testing investigational therapies as an alternative to rodent-induced
`cancers, which usually have limited relevance to man [ 45 ] .
` With developments in genetic engineering, speci fi c traits can be introduced into
`animals. So-called “knock-out” or “knock-in” animals can be engineered either to
`generate an animal with a genetic de fi ciency or alternatively to express a speci fi c
`gene in a form which provides insight into human disease. Although most trans-
`genic studies use inbred mice, rabbits [ 46 ] , sheep [ 47, 48 ] , pigs [ 49, 50 ] , chickens
` [ 51 ] , and non-human primates [ 52, 53 ] have been described.
`
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`

`16 Human: Veterinary Technology Cross Over
`
`363
`
` Genetic engineering is well established, for example, to make pest-resistant
`crops and to produce pharmaceuticals from bacteria. With respect to animals, the
`advantages of genetic engineering over conventional breeding methods include
`speed and speci fi city. This has led to “precision” breeding [ 54 ] with applications
`ranging from animals engineered as sources of “products” for medical applications,
`to pedigree companion animals. Current transgenic studies have developed, for
`example, mice with “human” cells or organs. Sentinel chimeric animals with
`enhanced sensitivity to pathogens or to environmental chemicals may even be cre-
`ated as “early warning” systems for human infectious diseases [ 55 ] .
` Transgenic animals (chimera or hybrids) may carry a human gene inserted into
`their genome using techniques of recombinant engineering. These include using
`stem cells (embryonic or adult) growing in tissue culture with the desired DNA or
`alternatively injecting the desired (human) gene into the pro-nucleus of a fertilized
`egg [ 56 ] . Either of these methods may be employed to generate animals which
`express human genes. Animals containing viable human tissues, cells, or genetic
`information have arisen through research which is aimed at generating animal mod-
`els of human disease, as well as to develop and produce new therapeutic entities.
`Not least due to ethical concerns, a controversy is under way [ 57, 58 ] . Applications
`of transgene technologies are vast in potential and range. For example, transgenic
`probiotica have been considered as a vector for targeted drug delivery [ 59 ] and vari-
`ous approaches have been investigated for gene transfer [ 60, 61 ] , an approach which
`when it matures may provide bene fi ts for human and animal patients alike. Similarly,
`use of siRNA with the potential to silence any targeted gene of interest [ 62 ] , in cer-
`tain pathologies caused by excessive or inappropriate gene activation, might equally
`bene fi t animal and human populations [ 63 ] .
` Yet another technique in which non-human animals may be engineered to pro-
`duce a human pharmaceutical has resulted in generation of a human protein, anti-
`thrombin, which was the fi rst “biological” made in a transgenic animal to receive
`regulatory approval for human therapy (ATryn® GTC Biotherapeutics, MA, USA).
`Speci fi cally, this approach harnessed another physiological advantage since the
`anti-thrombin is secreted in the milk of transgenic goats. This is further proof of
`principle that ef fi cient methods may be designed to produce biologically active
`human recombinant proteins in secreted animal fl uids.
`
` 16.4
`
` Drugs for Animal Use Developed in Humans
`
` One of the reasons for a relative reduction in numbers of animals in drug discovery
`has been increasing reliance on (human) cell-based assays. Cell-based approaches
` [ 64 ] , including high throughput screens [ 65, 66 ] , which have greatly accelerated the
`number of candidate drugs that can be evaluated for ef fi cacy and also for safety [ 67,
` 68 ] . Most pharmaceuticals currently used in animals were originally developed
`for human use, a major exception being the avermectins. In contrast, the microsomal
`triglyceride transfer protein inhibitor, Slentrol ® (Dirlotapide, P fi zer Animal Health,
`Groton, USA), is a drug which is restricted to use only in obese dogs [ 69 ] .
`
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`

`364
`
`A.W. Baird et al.
`
`Recent product approvals of new chemical entities follow this trend of speci fi c
`design for veterinary species. An example is the tyrosine kinase inhibitor, Palladia®
`(Toceranib, P fi zer Animal Health, Groton, USA), which was approved in 2009 for
`treating cutaneous mast cell tumors in dogs [ 70 ] . A recent development in the US is
`that a consortium made up of 19 veterinary schools is inviting owners to allow the
`use of investigational human cancer therapies in dogs expressing cancers before
`they have been approved for man and this is providing additional safety and ef fi cacy
`animal data as well as evidence of remission in some cases [ 71 ]
` However, formulations and dosages must be tailored according to speci fi c species
`needs and applications. Some aspects of drug use in animals therefore differ from
`their use in humans. For example, antibiotics have been employed as growth promot-
`ers in food animals, for which there are legitimate concerns over resistance genera-
`tion in man from drug residues. Regulations therefore mandate withdrawal periods
`between use of drug and slaughter for human consumption. For some drugs there are
`species-related patterns of sensitivity. Notwithstanding the general similarities
`between vertebrate species, drug absorption varies within as well as between species.
`Considering the anatomical differences between monogastrics, hindgut fermenters,
`foregut fermenters, and ruminants, the potential for differences in PK pro fi les is
`marked and this has led to different drug administration technologies in which, for
`example, device engineering advances have been dominant for intraruminal and
`intravaginal delivery in production