Drug bioanalysis pharmacokinetics

As bioanalysis plays a key role during drug discovery and toxico-kinetic/pharmacokinetic evaluation of drug candidates, several improvements have been made in minimizing the time spent in performing bioanalysis and for the evaluation of drug efficacy. 

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 quantitative determination of analytes in biological matrices such as blood, urine, etc. is called bioanalysis. Regulatory authorities and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance requires that the concentration-time profiles of drugs and/or metabolites in man or in animals are studied so their respective pharmacokinetics can be calculated and used as a basis for the evaluation of pre-clinical (especially toxicological) and clinical studies. 

Despite the everincreasing number of applications associated with pharmaceutical bioanalysis, strong emphasis continues to be placed on the analysis of plasma samples from live-phase studies. The reason for this demand is that the concentration of a drug in plasma is the well-accepted surrogate marker for drug exposure and is essential to the study of pharmacokinetics (PK) and toxicokinetics (TK). 

El-Kattan, A., Holliman, C., and Cohen, L.H., Quantitative bioanalysis in drug discovery and development Principles and applications, in Mass Spectrometry in Drug Metabolism and Pharmacokinetics, Ramanathan, R. (ed.), John Wiley Sons, Hoboken, NJ, 87, 2008. 

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. 

LC-MS determination of drugs and metabolites in clinical studies is a key function in the success and effectiveness of clinical development of drugs. LC-MS has established an obvious advantage for quantitative pharmacokinetic studies in terms of analysis time, cost, and sample throughput. LC-MS/MS has powerful capacity in quantity bioanalysis. LC-MS in clinical applications such as in the diagnosis of inherited and acquired metabolic disorders, gastrointestinal disorders, cancer and diabetes, and therapeutic dmg monitoring is still frequently required. 

With the increasing number, diversity, and complexity of compounds being analyzed, UPLC presents the possibility to extend and expand the utility of separation science. Today, UPLC is widely used for metabolite identification analysis of natural products and herbal medicines pharmacokinetic, toxicity, degradation, bioanalysis, and bioequivalence studies quality control and in drug discovery determination of pesticides and separation of various pharmaceutical-related small organic molecules, proteins, and peptides. UPLC is also used for impurity profiling, method development, and validation performed in quality assurance and quality control laboratories [46,47,56-69]. 

A pharmacokinetic study is composed of three phases, namely the in-life phase, bioanalysis, and data analysis. The in-life phase includes administering the compound to animals or humans and collecting samples from the appropriate matrix of interest such as blood or urine at predetermined time intervals for bioanalysis. The bioanalytical phase involves analysis of a drug and/ or its metabolite (s) concentration in blood, plasma, serum, or urine. This analysis typically involves sample extraction and detection of analytes using sensitive methods like LC/MS/MS. The third phase is data analysis using noncompartmental or compartmental pharmacokinetic computational methods. 

There are challenges to maximizing the exclusive patented lifetime of new medicines. It is, therefore, essential that compounds unlikely to reach the market are eliminated as early as possible (92). This demands the ability to make informed decisions regarding compounds in accordance with tight deadlines. A contributory part of the required information is a knowledge of the metabolism and pharmacokinetic properties of potential drug candidates with the implication that fast generic methods for pharmaceutical bioanalysis are essential (92). In a dmg discovery bioanalysis... 

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