The subject of metabolites in safety testing has had much debate in the recent past and has shown itself to be a complex issue with no simple solutions to providing absolute assurance of drug safety. Much of the attention has focused on the ability to identify metabolites and then demonstrate that their risk has been adequately characterized, either through their exposure in toxicology species or, failing this, by direct safety testing. In this review, we summarize our forward operational strategy that combines the principles summarized in the FDA Guidance, together with discussions at scientific meetings and literature opinions. It is a balance between the primary goal of assuring patient safety with one of reasonable investment. A key principle in striking this balance is to build stepwise information on metabolites through the drug discovery and development continuum. This allows assessments to be made from early nonclinical studies onward as to whether or not metabolite safety is underwritten by exposure in toxicology species. This strategy does not require absolute quantitation of the metabolites in early clinical trials but relies upon comparison of relative exposures between animals and humans using the capabilities of modern analytical techniques. Through this strategy, human disproportionate metabolites can be identified to allow a decision regarding the need for absolute quantitation and direct safety testing of the metabolite. Definitive radiolabeled studies would be initiated following proof of pharmacology or efficacy in humans, and nonclinical safety coverage would be adequately assessed prior to large-scale clinical trials. In cases where metabolite safety is not supported through the parent compound toxicology program, approaches for the direct safety testing of metabolites with regard to general and reproductive toxicology, safety pharmacology, and genetic safety have been defined.

When the Drug Metabolism Discussion Group was instigated in 1971, metabolite identification by mass spectrometry was a slow and laborious process undertaken by mass spectrometrists who seemed to continually disappoint their colleagues by failing to obtain the metabolite spectra. This was usually because not enough material was supplied or the material was impure. Today, accurate metabolite information can be obtained rapidly with little material by utilizing a range of mass spectrometers with complementary properties. This review will discuss how both technology and strategy have evolved over the past forty years to meet the changing demands of metabolism studies within the pharmaceutical industry.

HPLC detector technology has advanced dramatically over the past 20 years, with a range of highly sensitive and specific detectors becoming available. What is still missing from the bioanalyst's armoury, however, is a highly sensitive detector that gives an equimolar response independent of the compound. This would allow for quantification of compounds without the requirement for a synthetic standard or a radiolabeled analogue. In particular, such a detector applied to metabolism studies would establish the relative significance of the various metabolic routes. The recently issued US FDA guidelines on metabolites in safety testing (MIST) focus on the relative quantitation of human metabolites being obtained as soon as feasible in the drug-development process. In this article, current detector technology is reviewed with respect to its potential for quantitation without authentic standards or a radiolabel and put in the context of the MIST guidelines. The potential for future developments are explored.

The Oxford Handbook of Human Resource Management aims to provide an authoritative account of current trends and developments in Human Resource Management (HRM). HRM is central to management teaching and research, and has emerged in the last decade as a significant field from its earlier roots in personnel management, industrial relations, and industrial psychology. People Management and High Performance teams have become key functions and goals for managers at all levels in organizations. The text is divided into four parts: foundations and frameworks; core processes and functions; patterns and dynamics; and finally measurement and outcomes.

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