Safety attrition

Recognition of the importance of safety attrition and how it could be reduced by discover toxicology programs has only occurred recently. Thus, it is relatively new. 

Second, it must be able to detect chronic as well as acute toxicities, especially as it is the former that is the more common cause of safety attrition in the clinics. It is critical that cells be exposed to toxicants for sufficient time to allow expression of the cytotoxicity [6, 11, 14—16]. Three days of incubation of cells was effective for more than 95% human hepatotoxic drugs, whereas a single day of incubation was frequently ineffective [4] or produced cytotoxicity at a much higher concentration [4, 11, 14]. 

More recently, the bottleneck of drug research has shifted from hit-and-lead discovery to lead optimization, and more specifically to PK lead optimization. Some major reasons are (i) the imperative to reduce as much as feasible the extremely costly rate of attrition prevailing in preclinical and clinical phases, and (ii) more stringent concerns for safety. The testing of ADME properties is now done much earlier, i.e. before a decision is taken to evaluate a compound in the clinic. 

FIGURE 1.1. Attrition during the development of new molecules with a promise of therapeutic potential. Over the course of taking a new molecular entity through scale-up, safety and efficacy testing, and, finally, to market, typically only one out of every 9000 to 10,000 will go to the marketplace. 

The reasons for drug attrition have evolved over the years over the last decade, lack of safety (both non-clinical and clinical) remains the major cause of attrition during clinical development, which accounts for approximately 35 to 40% of all drug discontinuation (see Table 13.1).la lc More worrying is the fact that there is no clear trend toward a reduction of the attrition owing to safety reasons. 

Elutriation is important in most industrial fluidized beds and is generally thought of as a disadvantage. In addition to the small particles which may be present in the initial particle size distribution, fines may be created in the course of operation by the attrition of bed particles. Elutriated particles usually need to be collected and recovered either because they represent the loss of product particles of a given size, because they must be separated from the exhaust gas for environmental reasons, or because of safety concerns there is a considerable risk of a dust explosion with very fine particles and perhaps especially so with many food particulates. Therefore the fluidized bed plant will require ancillary gas cleaning equipment such as a cyclone, filter or electrostatic precipitator to separate the fines from the gas. The loss of a particular size fraction from the bed may change fluidized bed behaviour and it then becomes important to return the fines to the bed continuously. 

In Vitro Safety Pharmacology Profiling an Important Tool to Decrease Attrition... 

The high attrition rate of new chemical entities (NCEs) in preclinical and clinical phases can be attributed to many factors. According to Kola and Landis [50], NCEs fail mainly to insufficient efficacy, bioavailability, safety, toxicological and economic reasons. All these factors are somehow interrelated - a less soluble drug might be less bioactive and thus less efficient. Additionally, the attrition rate can depend on the therapeutic area the drug comes from. For example, compounds tend to fail more for CNS and oncology indications than in other therapeutic areas [50]. 

Lack of bioavailability and other adverse pharmacokinetic properties caused 40% attrition in 1992. However, this attrition was reduced by an order of magnitude by 2000 to 10%. This resulted in a substantial rise in the relative impact of adverse safety to one-third of attrition, whereas lack of efficacy had mildly less impact [1]. The basis of the decreased pharmacokinetic attrition may be reasonably attributable to the introduction of in vitro screening in drug discovery. 

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