By far, the most intense use of Liquid Chromatography and Mass Spectrometry (LC-MS) during the clinical development stage involves the quantitative bioanalysis of a drug, and the drug-related substances, in support of pharmacokinetic activities. Sensitive assays are of paramount importance to success, particularly because lead compounds are more potent and require smaller doses than before. The information obtained on impurities and degradants during the preclinical development stage provides a useful historical database. Thus, when significant process changes are made, the impurity profile is reviewed to determine whether the toxicological studies still support development. The LC-MS-based quantitative bioanalysis assay has emerged as the method of choice due to its high sensitivity and selectivity characteristics.
LC-MS Activities & Approaches
LC-MS analysis support activities dealing with alternative dosing formulations. The analysis plays a major role in the success, efficiency, and timeliness of clinical development. Two LC-MS-based methods SIM and SRM, are invaluable tools for quantitative analysis in clinical development.
By following the screening and identification of compounds along with concentrating on desirable activity, it is possible for laboratories to undertake the screening of drug candidates for desirable ADMET properties and set protocols to follow an integrated lead optimization and selection program. The design of such a program often requires consideration of several areas, including the number of molecular ‘hit’ candidates required to be optimized in the library.
In a given primary therapeutic area, the trend of working with a small molecular ‘hit’ library arises from awareness among scientists that the use of a mechanical, knowledge-based approach of integrating biology and chemistry as the potential to generate higher-quality ‘hits’. The process is more cost-effective when compared to earlier approaches in the use of combinatorial chemistry and high throughput screening approach.
A common LC-MS approach involves chromatography of an extracted sample, followed by electrospray ionization of the drug molecule. LC MS assay approach often relies on chromatographic separation of drug molecule from sample matrix components. The next steps include detection of the protonated molecular ion.
A single LC/MS/MS assay permitting simultaneous measurement of a mixture comprising five or six compounds is considered desirable. It helps to reduce the analytical data turnaround time and decreases the costs of assaying multiple samples because it is possible to pool samples collected from in vitro assays of five or six individual drug candidate. The LC/MS approach, experts believe, is suitable if adequate chromatographic separation among the drug candidates is achieved.
LC-MS In Drug Research and Discovery
The LC-MS assays have become an extremely useful analytical chemistry tool to accelerate the transition from discovery to the stages of preclinical development. The use of proper LC-MS assays in conjunction with proper in vitro and in vivo study designs can generate significant benefits. These results help in shortening timelines and reducing cost during the preparation of an Investigational New Drug application.
Regardless of in vitro or in vivo assay method the use of LC-MS assay method in support of ADMET investigations, the assay can directly generate significant benefits in reducing turnaround time and assay costs.