Drug development quantitative bioanalysis

In addition to these qualitative studies, quantitative bioanalysis, e.g., in preclinical and clinical studies to provide pharmacokinetic and pharmacodynamic data, is an essential part of drug development. Quantitative bioanalysis is the most important application area of LC-MS, in terms of number of instruments applied and the number of analyses performed. Fast, high-throughput, and routine quantitative analysis by LC-MS also demands fast and automated sample pretreatment strategies and advanced data-processing software. 

Hsieh S. et al., 2004. Increased throughput of parallel online extraction liquid chromatography /electrospray ionization tandem mass spectrometry system for GLP quantitative bioanalysis in drug development. Rapid Commun Mass Spectrom 18 285. 

Jemal M, Xia YQ. LC-MS development strategies for quantitative bioanalysis. Current Drug Metabolism 7, 491-502, 2006. 

Quantitative Bioanalysis in Drug Discovery and Development Principles and Applications... 

As shown in Fig. 2.7, quantitative bioanalysis supports the advancement of new chemical entities throughout the continuum of drug discovery and development. 

Although the scope of application continues to grow, the routine use of LC/MS technologies are now embraced by pharmaceutical researchers. Standard methods that incorporate highly specialized features are routinely developed for a variety of novel applications. Furthermore, many LC/MS applications that deal with quantitative bioanalysis (i.e., pharmacokinetics studies) are frequently outsourced to contract analytical laboratories. Thus, the routine use of LC/MS is a benchmarked commodity for drug development. 

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). 

Quantitative bioanalysis has been reported for a wide variety of drugs and their metabolites for various stages of drag development. In this section, procedures and results for five compounds (classes) are reviewed. The five compounds were selected, because a number of studies were reported for each compound. This allows to illustrate the diversity in strategies in quantitative bioanalysis. 

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