Prediction of Dose in Man

One of the most frequently used methods for predicting human pharmacokinetics from animal data is allometry. This technique was initially used to explain the relationship between body size and organ weights in animals [62-67]. The approach is based on finding a correlation between a physiological and the pharmacokinetic parameter of interest. Generally, the relationship takes the form of 

The allometric coefficient and exponent are determined empirically and are not thought to have any physiological correlate. 

The drawback of this approach is that it is essentially empirical and does not allow for differences in metabolic clearance between the species, that is, it assumes that clearance is proportional to blood flow. This works well for compounds that are highly extracted in the liver and/or where passive renal clearance is the maj or pathway [5,68]. An approach for compounds that are actively secreted into the urine has also been proposed [69], though the precise values of some of the physiological scaling factors have been questioned [70]. 

Unfortunately, when clearance is largely metabolic and low, allometry can significantly overpredict the human value [71]. Recent investigations have attempted to address this by combining allometric approaches with in vitro metabolism data [5]. 

A recent debate on allometric scaling has suggested that a great deal of further work is necessary before allometry can be used with confidence in a prospective manner. It is claimed that it is not possible to know in advance when allometry will not be suitable, and indeed the accuracy of the predictions may not be as reliable as assumed [72-74]. 

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The equation is an approximation, adapted from that for intravenous dosing [81], corrected by addition of a term for absorption. Essentially it assumes instantaneous absorption of the dose, but for compounds with reasonable physico-chemical and PK properties that are expected to be suitable for once-a-day dosing, this approximation makes little difference to the predicted value of Cmin ss. Use of the relationship can provide a simple approach for estimating the required dose in man for a compound in the discovery phase. 

Single-dose toxicity studies fall into two categories preliminary and definitive studies. Preliminary studies are performed to provide an estimate of the maximum nonlethal dosage (MNLD) for use in definitive studies. Definitive studies are performed to evaluate effects that may result from acute exposure to the MNLD and predict effects of overdosage in man. 

A number of mathematical models have been developed to describe the interplay of solubility and these physiological parameters to model dmg absorption. The most simplistic model is the maximal absorbable dose (MAD) calculation. The MAD calculation combines the amount of dmg that can dissolve to form a saturated solution in water equal in volume to the small intestinal volume, with an estimate of the absorption rate and the small intestinal transit time. The maximal absorbable dose is then related to the dose required to achieve the desired therapeutic effect [2], If the estimated MAD is much greater than the predicted dose to achieve a therapeutic effect, this can give confidence enough to take the dmg toward clinical use. Predictions of aqueous solubility may then be useful in predicting the extent of absorption in man. 

Alexanderson B (1972). Pharmacokinetics of nortriptyline in man after single and multiple oral doses the predictability of steady-state plasma concentrations from single dose plasma-level data. Eur JClin Pharmacol 4 82. 

As ADME/PK has become incorporated into drug discovery it has become necessary to reconsider the purpose of the studies. If the science is really going to reduce the attrition rate in development, then it is essential for the studies to allow predictions of the PK in man to be made. This means predicting the likely size and frequency of the dose. A review of the top 10 medicines of 1999 (Table 6.1) shows all of them to be once-a-day compounds. It is clear that to be best in class , and to be able to maintain that position as follow-up compounds come along, it seems probable that a compound will need to be suitable for once a day dosing. 

As stated in the Section 6.1, one of the principal purposes of carrying out DMPK studies during the discovery phase is to reduce the failure rate during development. For DMPK this logically means predicting the pharmacokinetics that will be observed and hence the dose that will be required in man when clinical studies are carried out. 

Based on all the above observations, we concluded that peripheral effects on the heart predict the lethal dose for belladonnoids better than do their central effects. This was apparently the case in animals such as the mouse, for which the LD50 had been previously established by direct measurement. EA 3443 and EA 3580, both of which have greater relative central potency in man than BZ, also were found to have higher safety margins in the mouse (and other species). 

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