Discovery safety assessment

Need to Coordinate Cytotoxicity Screening with Other Discovery Safety Assessments 327... 

Table 14.1 Potential contributory role of HCA in discovery safety assessment (see genotoxicity and cytotoxicity).

A technique called probabiUstic safety assessment (PSA) has been developed to analy2e complex systems and to aid in assuring safe nuclear power plant operation. PSA, which had its origin in a project sponsored by the U.S. Atomic Energy Commission, is a formali2ed identification of potential events and consequences lea ding to an estimate of risk of accident. Discovery of weaknesses in the plant allows for corrective action. 

Once past the discovery and initial development stages, the safety assessment aspects of the process become extremely tightly connected with the other aspects of the development of a compound, particularly the clinical aspects. These interconnections are coordinated by project management systems. At many times during the early years of the development process, safety assessment constitutes the rate-limiting step it is, in the language of project management, on the critical path. 

It is important to keep in mind that safety assessment is only one of many components involved in the discovery and development of new pharmaceuticals. The entire process has become enormously expensive, and completing the transit of a new drug from discovery to market has to be as efficient and expeditious a process as possible. Even the narrow part of this process (safety assessment) is dependent on many separate efforts. Compounds must be made, analytical and bioanalytical methods developed, and dosage formulations developed, to name a few. One needs only to refer to Beyer (1978), Hamner (1982), Matoren (1984), Sneader (1986) (a good short overview), Zbinden, (1992) or Spilker (1994) for more details on this entire process and all of its components. 

There are multiple phases involved in the safety assessment portion of the discovery, development and marketing process. The actual conduct of the studies in each phase forms the basis of the bulk of the chapters in this book. However, unless... 

Lynch A, Connelly J. Drug discovery and development the toxicologist s view - non-chnical safety assessment. In Martin R WiUdns, ed. Experimental Therapeutics. London Martin Dunitz, 2003 25-50. 

Moggs JG, Goodman JJ, Trosko JE, et al. Epigenetics and cancer implications for drug discovery and safety assessment. Toxicol AppI Pharmacol 2004 196 422-430. 

Frequently, a simple approach of pH adjustment or cosolvent is not enough to achieve the target concentration. Cosolvents are often used in combination with pH adjustment to further enhance the solubility. Using this approach, Lee et al. (2003) observed that nearly 85% of PLzer, Ann Arbor discovery compounds (> 300) submitted for discovery and preclinical injectable formulation development in the year 2000 could be formulated by pH adjustment, cosolvent addition, or a combination of the two approaches. It was also observed that 11% of compounds were not formulatable using this approach, and another32% ofthe formulation used more than 55% cosolvent. The high solvent content can limit the pertinent safety assessment of lead compounds. Therefore, the synergistic combinations of pH adjustment and cosolvent are not sufLcient to develop commercially... 

Turner JR, Durham TA. Nonclinical Development Integrated Cardiac Safety Assessment Methodologies for Non-cardiac Drugs in Discovery, Development, and Postmarketing Surveillance. John Wiley Sr Sons Inc. Hoboken, New Jersey. 2009 111-134. 

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