Drug development sensitivity analysis

A high-sensitivity cell for the Agilent Capillary Electrophoresis System has recently been developed. The cell increases detection sensitivity by an order of magnitude compared to standard detection [61]. This new cell is expected to increase substantially the utility of CE/CEC for the detection of enantiomeric purity of chiral drugs and trace analysis in biological and environmental samples. 

An important aspect of the drug development process is that in early developmental phases the analysis is directed at a relatively small number of samples of a wide variety of compounds, while at a later stage the number of analytes is significantly reduced but the number of samples to be analysed per compound increases exponentially. Routinely applicable, robust, and sensitive analytical methods are required in the various phases of the process. 

An additional component of the PK model that may warrant consideration in the simulation is the relative bioavaUabUity of the drug formulation to be used in the efficacy trial. Formulation changes may occur at this point in development, where a suboptimal formulation for commercial-scale manufacture may have been used in previous studies. If such changes have occurred between the dose-ranging study and current design, the relative bioavailabiUty between formulations (and associated 90% Cls) may also be considered for simulation evaluation. A sensitivity analysis (see Section 35.3.1) may be conducted to evaluate whether this effect will be influential on the simulation and/or if additional data may be required to provide acceptable precision. 

Nuclei that are typically analyzed with this technique include those of 13C, 31P, 1SN, 2SMg, and 23Na. Different crystal structures of a compound can result in perturbation of the chemical environment of each nucleus, resulting in a unique spectrum for each form. Once resonances have been assigned to specific atoms of the molecule, information on the nature of the polymorphic variations can be obtained. This can be useful early in drug development, when the single-crystal structure may not be available. Long data acquisition times are common with solid-state NMR, so it is often not considered for routine analysis of samples. However, it is usually a very sensitive technique, and sample preparation is minimal. NMR spectroscopy can be used either qualitatively or quantitatively, and can provide structural data, such as the identity of solvents bound in a crystal. 

Another current trend that is well underway is the use of more specific analytical instrumentation that allows less extensive sample preparation. The development of mass spectrometric techniques, particularly tandem MS linked to a HPLC or flow injection system, has allowed the specific and sensitive analysis of simple extracts of biological samples (68,70-72). A similar HPLC with UV detection would require significantly more extensive sample preparation effort and, importantly, more method development time. Currently, the bulk of the HPLC-MS efforts have been applied to the analysis of drugs and metabolites in biological samples. Kristiansen et al. (73) have also applied flow-injection tandem mass spectrometry to measure sulfonamide antibiotics in meat and blood using a very simple ethyl acetate extraction step. This important technique will surely find many more applications in the future. 

As demonstrated by Fig. 17.1-7 in the above application to the f AK-STAT pathway, sensitivity analysis can contribute to the identification of drug targets facilitating the early stages of drug development. 

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