Safety pharmacology in pharmaceutical development and approval

199 Pages·2004·2.532 MB·English

by  Shayne C Gad

Second Edition
Safety
Pharmacology
in Pharmaceutical
Development
Approval and Post Marketing
Surveillance

Second Edition
Safety
Pharmacology
in Pharmaceutical
Development
Approval and Post Marketing
Surveillance
Shayne C. Gad
Boca Raton London New York
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Version Date: 20120320
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Dedication
To Novie Beth—
for bringing so much
light and joy
to this life

Contents
Preface..................................................................................................................xi
About.the.Author..............................................................................................xv
Chapter 1 Safety pharmacology: Background, history, issues,
and concerns ................................................................................1
1.1. General.versus.safety.pharmacology....................................................2
1.2. History........................................................................................................4
1.3. Reasons.for.poor.predictive.performance.............................................7
1.4. Why.tiers?..................................................................................................8
1.5. Study.designs.and.principles..................................................................9
1.5.1. Selection.of.methodology.and.species....................................9
1.6. Issues........................................................................................................12
1.7. Integral.versus.separate.........................................................................13
1.8. Summary.................................................................................................15
References..........................................................................................................15
Chapter 2 Regulatory requirements: ICH, FDA, EMA, and Japan .....19
2.1. Regulatory.requirements.......................................................................19
References..........................................................................................................23
Chapter 3 Principles of screening and study design ............................25
3.1. Introduction.............................................................................................25
3.2. Characteristics.of.screens......................................................................27
3.3. Uses.of.screens........................................................................................30
3.4. Types.of.screens......................................................................................32
3.5. Criterion:.Development.and.use..........................................................32
3.6. Analysis.of.screening.data....................................................................35
3.6.1. Univariate.data..........................................................................35
3.6.1.1. Control.charts...........................................................35
3.6.1.2. Central.tendency.plots............................................37
3.6.2. Multivariate.data......................................................................38
3.6.2.1. Analog.plot...............................................................39
3.7. Study.design............................................................................................41
vii
viii Contents
3.7.1. Animal.model...........................................................................41
3.7.2. Group.size..................................................................................42
3.7.3. Statistical.design.......................................................................42
3.7.3.1. Dose.levels.and.test.concentrations......................42
References..........................................................................................................42
Chapter 4 Cardiovascular system .............................................................45
4.1. Introduction.............................................................................................45
4.2. History......................................................................................................45
4.2.1. Special.case.(and.concern)—QT.prolongation.....................45
4.2.1.1. Regulatory.developments.......................................47
4.2.2. Patch-clamp.studies.using.recombinant.cells.
expressing.hERG.channels......................................................57
4.2.3. hERG.protein.expression.system............................................57
4.2.3.1. Relevance.of.hERG.to.QT.prolongation................58
4.2.3.2. Expression.and.recording.systems........................58
4.2.4. Cardiovascular.function.testing.............................................59
4.2.5. Conscious.rodent,.dog,.and.primate.telemetry.studies......64
4.2.5.1. Six-lead.ECG.measurement.in.the.
conscious.dog...........................................................64
4.2.6. Systems.for.recording.cardiac.action.potentials..................65
4.2.6.1. Cloned.human.potassium.channels.....................65
4.2.6.2. Cardiac.action.potential.in vitro—Purkinje.
fibers..........................................................................65
4.2.6.3. Monophasic.action.potential.in.anesthetized.
guinea.pigs................................................................65
4.2.6.4. ECG.by.telemetry.in.conscious.guinea.pigs........65
4.2.6.5. Hemodynamics.and.ECG.in.anesthetized.
or.conscious.dogs.or.primates...............................66
4.3. Summary.................................................................................................66
References..........................................................................................................66
Chapter 5 Central nervous system ...........................................................69
5.1. Core.battery.CNS.procedures...............................................................72
5.1.1. General.behavioral.observation.............................................72
5.1.2. Functional.observational.battery...........................................73
5.2. Rat.............................................................................................................74
5.2.1. Observational.assessments.....................................................74
5.2.2. Locomotor.activity....................................................................75
5.2.3. Motor.coordination..................................................................75
5.2.4. Pain.sensitivity..........................................................................76
5.2.5. Convulsive.threshold...............................................................76
5.3. Dog............................................................................................................77
5.3.1. Neurobehavioral.screen...........................................................77