The Four Stages of Drug Development

Drug development has become more complex and highly competitive while the sample analysis contributions have become increasingly important. This perspective recognizes the impact of sample analysis activities and the corresponding information that must be accumulated throughout the various stages of development. 

TABLE 2.1 The four stages of drag development and their corresponding milestone and analysis emphasis 

Development stage Milestone Analysis Emphasis LC/MS Analysis Activities 

Drug discovery Lead candidate Screening Protein identification natural products identification metabolic stability profiles molecular weight determination for combinatorial/ medicinal chemistry support. 

Preclinical development IND/CTA filing Evaluation Impurity, degradant, and metabolite identification. 

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Following is a brief summary of the four stages of drug development. Significant events are highlighted with respect to their relationship to analysis requirements. 

TABLE 5.2 Applications of LC/IMS that highlight the use of a specific strategy within the four stages of drug development... 

FIGURE 2.3 An overview of the drug development process that illustrates the activities within the four major stages of drug development drug discovery, preclinical development, clinical development, and manufacturing. (Courtesy of Milestone Development Services, Newtown, PA, 1998. With permission.)... 

The first stages of development of the modern pharmaceutical industry can be traced back to the turn of the twentieth century. At that time (apart from folk cures), the medical community had at their disposal only four drugs that were effective in treating specific diseases ... 

The use of SRM methods for quantitative bioanalysis represents increased dimensions of mass spectrometry analysis. SRM methods that use APCI-LC/MS/MS for the quantitative analysis of an antipsychotic agent, clozapine, in human plasma were described by Dear and co-workers (Dear et al., 1998). Preclinical development studies of clozapine in rats and dogs used HPLC with fluorescence detection (FLD). With this method, a better limit of quantitation (LOQ) of 1 ng/mL was obtained. As the compound moved into the clinical stages of development, a more sensitive method of analysis was required to obtain rapid metabolic information in support of drug safety evaluation studies. A standard LC/MS/MS method is used for the quantitative analysis of clozapine (I) and four metabolites (II-V) in human plasma (Figure 6.34). 

A new, so-called third generation of antipsychotics has recently been introduced, and at this time one drug, aripiprazole, is available and others are in the late stages of development. This new class of medications has a novel mechanism of action that, at least in theory, should deal with several of the limitations of other atypicals. It will be remembered that all antipsychotics preceding this class had the ability to block the dopamine receptor, and they did so in all four dopamine pathways. As discussed, this had both benefits and drawbacks dopamine blockade resulted in the improvement of positive symptoms (mesolimbic pathway) but had a limited benefit in negative symptom reduction (mesocortical... 

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