Safety Pharmacology in Pharmaceutical Development and Approval
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Summary
The Propulsid and Seldane drug disasters could have easily been avoided with more rigorous safety pharmacology studies of these compounds prior to any human clinical trials. Unfortunately, safety pharmacology has been overlooked by all but a few developers. With recent drug withdrawals from the market and the implementation of the International Conference on Harmonization (ICH) guidelines, safety pharmacology will become a more important phase in drug development.
Safety Pharmacology in Pharmaceutical Development and Approval spells out the whys and hows of safety pharmacology testing. The book covers the background, history, and concerns that have evolved from lackluster safety pharmacology activities in the past. It details regulatory requirements, provides comprehensive information on study designs, and covers both the required battery of studies and the supplemental, follow-up battery.
Until recently, pharmacovigilance has been product-rather than utilization-oriented and often invisible in clinical medicine. It is clear that definitive safety pharmacology standards are needed to combat the increase in adverse reactions seen in the last 20 years. Giving you a head start in this emerging field, Safety Pharmacology in Pharmaceutical Development and Approval addresses how best to implement ICH safety standards and how to integrate pharmacology safety evaluations into existing safety evaluations.
Table of Contents
SAFETY PHARMACOLOGY: BACKGROUND, HISTORY, ISSUES, AND CONCERNS
General vs Safety Pharmacology
History
Reasons for Poor Predictive Performance
Why Tiers?
Study Designs and Principles
Issues
Summary
References
REGULATORY REQUIREMENTS OF ICH, U.S. FDA, EMEA, AND JAPAN MHW
Regulatory Requirements
References
PRINCIPLES OF SCREENING AND STUDY DESIGN
Introduction
Characteristics of Screens
Uses of Screens
Types of Screens
Criterion: Development and Use
Analysis of Screening Data
Univariate Data
Multivariate Data
Study Design
References
CARDIOVASCULAR SYSTEM
Introduction
History
Regulatory Developments
Summary
References
CENTRAL NERVOUS SYSTEM
Core Battery CNS Procedures
References
RESPIRATORY SYSTEM
Plethysmography
Design of Respiratory Function Safety Studies
Summary
References
RENAL FUNCTION
Major Functions of the Kidney
Acute Renal Failure (ARF)
Functional Reserve of the Kidney
Clearance
Free Water Clearance and Renal Concentrating Ability
Clinical Chemistry Measures
Animal Models
References
THE GASTROINTESTINAL SYSTEM
Drug-Induced Alterations of GI Transit or Motility
GI Function
Assessment of Intestinal Transit
Determination of Intestinal Absorption
Conclusions
References
SAFETY PHARMACOLOGY OF THE IMMUNE SYSTEM
Introduction
PCA Test for Potential Antigenicity of Compound
Overview of the Immune System
Immunotoxic Effects
Immunosupression
References
INTEGRATION OF EVALUATIONS INTO OF SAFETY PHARMACOLOGY into Existing Study Designs
Rodent Acute Toxicity
Nonrodent Acute Toxicology
Repeated Dose (IND Pivotal Toxicity) Studies
Integration
References
Selected regulatory and Toxicological Acronyms
Safety Pharmacology Labs
Index
Editorial Reviews
"[This] is the first book ever describing the specialty 'Safety Pharmacology' and it is a major contribution to understanding the increasing and demanding step from testing in animals to testing in humans. … Gad's book is an excellent summary of the ideas on the way to deal with safety pharmacology tests in drug development processes. It gives a good overview of ideas and testing strategies combined with many examples. … I can highly recommend reading the book … . It would make an admirable primer for safety pharmacologists, toxicologists, and people engaged with preclinical testing."
- BTS Newsletter
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