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models [63] are used to calculate more accurately the first dose to man and thus to minimize the number of dose escalations [64]. |
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One must question that if this is not done more frequently for all drugs then how relevant are animal safety studies? Certainly it is now well accepted that dosages cannot be compared from one species to another due to allometric differences in the rates of clearance, but similarly, we must not now simply accept plasma levels. |
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For example, it is assumed that the uptake into tissues is relatively the same for all species but this has never been systematically studied, presumably because of the difficulty of measuring the levels in humans. Recently, we have investigated the uptake of dexfenfluramine and its active metabolite into the brain of several species, including humans, and found that this is also dependent on the weight of the animal, such that the uptake by small rodents is four to six times higher than that in man (see details later) [48]. This has also been reported for other compounds, such as fluoxetine, and cannot simply be explained by differences in plasma protein binding. But how is it possible to measure the tissue kinetics in humans and can these difficulties by overcome? |
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Interrelating kinetic-dynamic data using nonlinear sigmoidal Emax models are now relatively easy to deal with because of the availability of computer programs. Thus data from animal studies can be rapidly assessed and used to compare from one species, strain, condition, etc. to another. This straightforward approach can be used for the majority of cases, even when multiple receptors are used [61,65], but it does assume that the drug is immediately in equilibrium with the receptor site and that there are few feedback controlling influences. To overcome the problem of hysteresis, when activity is not directly associated temporally with circulating drug levels, Sheiner and co-workers [66] have proposed the use of parametric models and nonparametric models [67] that link an effect compartment with a dynamic response. These methods are available using various computer programmes such as SIPHAR [68], PCNONLIN [69], ADAPT [70], TOPFIT [71], etc. With these models, it is possible to combine the changing kinetic profile with the dynamic activity, even if they are not directly in parallel. However, their very simplicity reduces their usefulness in describing the more complex drug effect that can occur. |
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B. Physiological Systems Modeling |
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The body is not a series of unrelated receptors and, although the empirical Emax models may be a useful starting point in describing drug action, they are gross oversimplifications of the real systems involved. Guyton, many years ago, |
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