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Apart from a wide range of pharmacokinetic and metabolism information, generally obtained in two or more animal species, an IND application contains an increasing proportion of toxicokinetic data. In fact the relatively new discipline of toxicokinetics, which has been the topic of several recent reviews [10,11], has emerged as a major component of pharmacokinetics and metabolism support to the IND and also the new drug application (NDA) for marketing. It is now generally accepted that toxicology studies need to be conducted on a concentration-effect rather than a dose-effect basis and toxicokinetics and/or drug monitoring, depending on the circumstance, is now an integral (and expensive) component of essentially all toxicology studies [12]. Despite some obvious, and some perhaps less obvious, shortcomings to the assumption of a simple relationship between circulating drug levels and observed toxic effects [13,14], a considerable amount of useful information can nonetheless be derived from observed toxicokinetic-toxicodynamic relationships. |
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Toxicokinetic studies conducted early in a toxicology program are useful in order to provide complete kinetic profiles at toxicological doses in appropriate animal species, to guide subsequent dose regiments in longer term toxicology studies, to establish concentration-effect relationships at an early stage, to establish systemic drug bioavailability at toxicological dose levels, and to characterize saturation processes. Needless to say the toxicokinetic characteristics of a drug might differ from the pharmacokinetic characteristics due to differences in administered dose size and the resulting circulating drug and/or metabolite levels. Thus, the handling of toxicokinetic studies, and also the kinetic and metabolism results obtained, may be expected to differ in terms of compound solubility and stability, rate and extent of absorption, the degree of presystemic metabolism, rate and pathways of metabolism, and protein binding. In fact, any saturable process is likely to be influenced to some extent, contributing to differences between toxicokinetic and pharmacokinetic behavior. |
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Pharmacokinetic studies, and associated studies of pharmacokinetic-pharmacodynamic relationships, differ from toxicokinetic studies and associated toxicokinetic-toxicodynamic relationships in one other important aspect. Pharmacokinetic-pharmacodynamic relationships are frequently based on well characterized pharmacodynamic endpoints such as blood pressure, heart rate, etc., while toxicokinetic-toxicodynamic relationships are just as frequently based on unpredictable, poorly defined, and poorly understood toxicological end-points. While preclinical pharmacokinetic-pharmacodynamic relationships are thus relatively easy to obtain, the nature of the relationship is unlikely to have a major impact on decisions to take the drug into humans. On the other hand, while toxicokinetic-toxicodynamic relationships are invariably difficult to obtain, and often even more difficult to understand mechanistically, these data are often critical for decisions as to whether or not the compound is safe to go into clinical trials. This paradox underscores the deemphasis that must occur |
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