Safety pharmacology in pharmaceutical development and approval

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 © 2004 by CRC Press LLC 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 © 2004 by CRC Press LLC 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 © 2004 by CRC Press LLC 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