Safety Pharmacology in Pharmaceutical Development and Approval

186 Pages·2003·1.91 MB·English

by  Shayne C. Gad

Safety
Pharmacology
in Pharmaceutical
Development
and Approval
© 2004 by CRC Press LLC
Safety
Pharmacology
in Pharmaceutical
Development
and Approval
Shayne C. Gad
CRC PR ESS
Boca Raton London New York Washington, D.C.
© 2004 by CRC Press LLC
Library of Congress Cataloging-in-Publication Data
Gad, Shayne C., 1948-
Safety pharmacology in pharmaceutical development and approval / Shayne C. Gad.
p. ; cm.
Includes bibliographical references and index.
ISBN 0-8493-1380-5
1. Drugs(cid:151)Toxicology. 2. Drugs(cid:151)Safety measures. I. Title.
[DNLM: 1. Drug Evaluation, Preclinical. 2. Drug Approval. 3. Toxicity Tests. QV 771
G123s 2003]
RA1238.G333 2003
615¢.704(cid:151)dc21 2003051468
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© 2004 by CRC Press LLC
Dedication
To my beloved Joyce
© 2004 by CRC Press LLC
Contents
Chapter 1 Safety pharmacology: background, history, issues,
and concerns.....................................................................................1
General vs. safety pharmacology.........................................................................2
History......................................................................................................................3
Reasons for poor predictive performance..........................................................6
Why tiers?................................................................................................................7
Study designs and principles...............................................................................8
Selection of methodology and species.....................................................11
Issues.......................................................................................................................12
Integral vs. separate....................................................................................13
Summary................................................................................................................14
References...............................................................................................................15
Chapter 2 Regulatory requirements of ICH, U.S. FDA, EMEA,
and Japan MHW............................................................................17
Regulatory requirements.....................................................................................17
References...............................................................................................................21
Chapter 3 Principles of screening and study design................................23
Introduction...........................................................................................................23
Characteristics of screens.....................................................................................25
Uses of screens......................................................................................................28
Types of screens....................................................................................................29
Single stage...................................................................................................29
Sequential.....................................................................................................30
Tier or multistage........................................................................................30
Criterion: development and use.........................................................................30
Analysis of screening data..................................................................................32
Univariate data......................................................................................................33
Control charts..............................................................................................33
Central tendency plots...............................................................................34
Multivariate data..................................................................................................36
The analog plot............................................................................................36
Study design..........................................................................................................37
Animal models............................................................................................39
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Group size....................................................................................................39
Statistical design..........................................................................................40
Dose levels/test concentrations................................................................40
References...............................................................................................................40
Chapter 4 Cardiovascular system.................................................................43
Introduction...........................................................................................................43
History....................................................................................................................43
Special case (and concern) — QT prolongation...................................43
Regulatory developments....................................................................................45
Patch-clamp studies using recombinant cells expressing
HERG channels..................................................................................55
HERG protein expression system.............................................................55
Relevance of HERG to QT prolongation.......................................56
Cardiovascular function testing................................................................57
Hemodynamics, EKG, and respiration in anesthetized dogs
or primates..........................................................................................59
Cardiac conduction studies.......................................................................59
Conscious rodent, dog, and primate telemetry studies.......................59
Six-lead EKG measurement in the conscious dog.................................60
Systems for recording cardiac action potentials....................................60
Summary................................................................................................................61
References...............................................................................................................62
Chapter 5 Central nervous system...............................................................65
Core battery CNS procedures.............................................................................67
General behavioral observation................................................................67
Functional observational battery..............................................................68
Observational assessments...............................................................68
Locomotor activity......................................................................................69
Motor coordination.....................................................................................70
Pain sensitivity.............................................................................................70
Convulsive threshold..................................................................................71
Sleep induction and interaction with hypnotics....................................71
Higher cognitive function..........................................................................71
Passive avoidance.......................................................................................72
Morris maze.................................................................................................72
Isolated tissue assays..................................................................................74
Electrophysiology methods.......................................................................76
CNS function: electroencephalography...................................................76
Neurochemical and biochemical assays..................................................77
References...............................................................................................................78
Chapter 6 Respiratory system.......................................................................81
Plethysmography..................................................................................................86
Design of respiratory function safety studies..................................................88
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General considerations...............................................................................88
Study design................................................................................................89
Capnography...............................................................................................90
Study design considerations.....................................................................90
Dose selection.....................................................................................90
Species selection.................................................................................91
Summary................................................................................................................91
References...............................................................................................................91
Chapter 7 Renal function...............................................................................95
Major functions of the kidney............................................................................96
Acute renal failure (ARF)....................................................................................97
Functional reserve of the kidney.......................................................................97
Clearance................................................................................................................97
Free water clearance and renal concentrating ability...................................102
Renal blood flow.......................................................................................104
Fractional excretion of sodium...............................................................104
Clinical chemistry measures.............................................................................104
Enzymuria..................................................................................................104
Proteinuria..................................................................................................104
Glucosuria..................................................................................................104
Urine concentration test...........................................................................105
Animal models....................................................................................................105
The rat.........................................................................................................105
The dog.......................................................................................................106
Cautions:.....................................................................................................106
Examples of species differences in drug sensitivity............................106
References.............................................................................................................107
Chapter 8 The gastrointestinal system......................................................109
Drug-induced alterations of GI transit or motility.......................................110
GI function...........................................................................................................111
Assessment of intestinal transit........................................................................112
Determination of intestinal absorption...........................................................113
Methods of administering test substance.............................................114
Methods for quantitating degree of absorption...................................115
Appearance in systemic fluids......................................................115
Gastric emptying rate and gastric pH changes: a new model..........117
Effects of drugs on gut immune system (jejunum, ileum, colon)....118
Candidate drugs to evaluate for effects on gut immune system.....118
Conclusions..........................................................................................................119
References.............................................................................................................119
Chapter 9 Safety pharmacology of the immune system........................123
Introduction.........................................................................................................123
PCA test for potential antigenicity of compound.........................................125
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Test method......................................................................................127
CDER guidance for investigational new drugs...................................128
Overview of the immune system.....................................................................129
Immunotoxic effects...........................................................................................136
Immunosuppression...........................................................................................137
Immunosuppressive drugs......................................................................138
Antimetabolites..........................................................................................138
Glucocorticosteroids.................................................................................141
Cyclosporine..............................................................................................142
Nitrogen mustards....................................................................................142
Estrogens.....................................................................................................143
Heavy metals.............................................................................................143
Antibiotics..................................................................................................144
Immunostimulation..................................................................................144
Hypersensitivity........................................................................................144
Type I...........................................................................................................147
Type II.........................................................................................................148
Type III........................................................................................................148
Type IV........................................................................................................149
Photosensitization.....................................................................................150
Autoimmunity...........................................................................................151
References.............................................................................................................155
Chapter 10 Integration of evaluations of safety pharmacology
endpoints into existing study designs...................................161
Rodent acute toxicity..........................................................................................162
Nonrodent acute toxicology..............................................................................163
Repeated dose (IND pivotal toxicity) studies................................................166
Body weight...............................................................................................166
Clinical signs..............................................................................................167
Clinical pathology.....................................................................................168
Pharmacokinetics and metabolism.........................................................168
Integration............................................................................................................172
References.............................................................................................................174
Selected regulatory and toxicological acronyms.........................................177
Safety pharmacology labs................................................................................181
© 2004 by CRC Press LLC
Preface
Safety pharmacology is the evaluation and study of the pharmacological
effects of a potential drug that are unrelated to the desired therapeutic effect
and, therefore, may present a hazard — particularly in individuals who
already have one or more compromised or limited organ system functions.
Unlike other nonclinical evaluations of a drug’s safety, these evaluations are
usually conducted at doses close to the intended clinical dose. Recent Inter-
national Conference on Harmonization (ICH) guidelines, followed by ver-
sions by national regulatory authorities including those of the U.S. Food and
Drug Administration (FDA), have made such evaluations mandatory before
a potential drug is introduced into humans — while also failing to provide
clear guidance as to how the requirements are to be met.
General/safety pharmacology has been an emerging discipline within
the pharmaceutical industry in which unanticipated effects of new drug can-
didates on major organ function (i.e., secondary pharmacological effects) are
critically assessed in a variety of animal models. A survey was conducted to
obtain customer input on the role and strategies of this emerging discipline.
Overlooked in importance by all but a few (Zbinden, 1966, 1984)* for many
years, the Japanese clearly became the leaders in developing and requiring
such information, while the U.S. was (and remains) in a position behind Japan
and the European Union (EU) in establishing formal requirements and in
implementing industrial programs. Most companies have traditionally con-
ducted evaluations of cardiovascular and central nervous system (CNS) func-
tions, while few have evaluated respiratory, gastrointestinal, and renal func-
tions; a few conduct a ligand-binding/activity panel as part of their
pharmacological profiling. Resources needed to complete a company’s stan-
dard safety pharmacology program are approximately one to four full-time
persons per compound. One-third of companies use a maximum tolerated
dose (MTD) for safety pharmacology studies; two-thirds use multiples of
pharmacological or therapeutic doses. Until 2000, only half conducted safety
pharmacology studies with Good Laboratory Practices (GLPs), using the 1992
Japanese guidelines as a guide or outline. Company clinicians were most
often cited as the primary customers for whom safety pharmacology studies
were done, followed by research and development scientists, and then
* Chapter 1, References 19 and 20.
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regulatory authorities. These results suggest that most companies primarily
conducted safety pharmacology for its contribution to risk assessment and
critical care management.
It is important that the tests employed detect bidirectional drug effects
and that the tests performed be validated in both directions with appropriate
reference (control) substances. This requirement is less appropriate for multi-
parameter procedures. Blind testing could be an advantage. Ethical consid-
erations are important, but the ultimate ethical criterion is the assessment of
risk for humans. Safety pharmacology studies should not be overly inclusive,
but should be performed to the most exacting standards, including GLP
compliance. This is, of course, backward; such human tolerance is properly
an extension (and expression) of the nonclinical safety pharmacology.
The other point of view has been that properly executed, repeated-dose
preclinical safety studies meeting the current design will (or could) fill these
needs, recognizing that undesired pharmacological activities of novel drugs
or biologicals may limit development of a therapeutic agent prior to the
characterization of any toxicological effects. In rodent species, general phar-
macology assays have traditionally been used to screen new agents for
pharmacological effects on the central and peripheral nervous systems, the
autonomic nervous system and smooth muscles, the respiratory and cardio-
vascular systems, the digestive system, and the physiological mechanisms
of water and electrolyte balance. In large animal species, such as dogs and
nonhuman primates, smaller numbers of animals per study limit their use
for screening assays, but these species may play an important role in more
detailed mechanistic studies. For drugs and biologicals that must be tested
in nonhuman primates because of species-specific action of the test agent,
functional pharmacology data are often collected during acute or subacute
toxicity studies. This requires careful experimental design to minimize any
impact that pharmacological effects or instrumentation may have on the
assessment of toxicity. In addition, with many new therapies targeted at
immunological diseases, the pharmacological effect of therapeutics on the
immune system presents new challenges for pharmacology profiling. The
applications of pharmacology assays by organ system in both rodent and
large animal species are discussed, as well as practical issues in assessing
pharmacological endpoints in the context of toxicity studies (Martin et al.
1997; Matsuzawa et al. 1997).*
In Europe, the numbers of registered drugs and drug expenditure are
increasing rapidly. Within the EU, there are no longer any regulations requir-
ing that new drugs have to be better than old ones. At the same time,
pharmacoepidemiology studies in Europe and the U.S. show that adverse
drug reactions now may account for up to 10% of the admissions of patients
to hospitals at a cost of hundreds of millions of U.S. dollars annually (Sjouist,
2000)**. Compared to 20 years ago, this represents a considerable increase.
* Chapter 1, References 37 and 38, respectively.
** Chapter 1, Reference 39.
© 2004 by CRC Press LLC