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suggest that both population kinetics and minimal sampling techniques with suitable validation would be acceptable to the regulatory authorities. |
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Regulatory requirements continue to increase despite harmonization, and kinetics may speed up drug development by bridging the gaps of knowledge between disciplines. But we have witnessed over the past few years some dramatic changes in biodisposition methodology and an understanding of what is important: improved analytical techniques, in vitro metabolism, enzyme expression, scaling, computational methods, and, for the first time, a core harmonized guideline for the acquisition of kinetic data from animal safety studies. These changes have allowed scientists to reassess what and when information is required. Some basic kinetics in a few animals can be obtained early in drug development but detailed ADME studies in multiple animal studies should be avoided unless undertaken to explain a particular problem. Emphasis on biodisposition studies must now be put into drug discovery, candidate choice, and getting into man as soon as possible. New predictive methods outlined here should be employed wherever possible to increase our knowledge of what is possible, and together with population approaches, all generated data on a new medicine should be interrelated to build up a complete and integrated profile. Perhaps the most exciting aspect of the future is the chance to make plasma concentrations more meaningful. They should not continue to be some undefined surrogate endpoint, but should be related to the activity at the site of action as early as possible in all preclinical studies, building on physiological systems control so that we can use pharmacological and toxicological pharmacokinetic-pharmacodynamic modeling and define more accurately the type of medicine and the dose for the individual patient. Kinetics, one of the youngest of the disciplines, is finally growing up and is being understood and accepted within the family of drug development. |
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I would like to thank Danielle Bowra for her artistic acumen and for patiently putting this paper together. |
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1. S. Walker. On file Center for Medical Research Surrey UK, 1993. |
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2. J. A. DiMasi. Success rates for new drugs entering clinical testing in the United States. Clinical Pharmacology Therap. 58: 114, 1995. |
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3. D. B. Campbell and R. Jochemsen. Nonclinical pharmacokinetics and toxicokinetics. In International Pharmaceutical Product Registration: Aspects of Quality, |
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