CR TidBit – Allometric Issues In Drug Development

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Allometry is one of the most frequently used methods for predicting pharmacokinetics from animal data. The most important objective of allometric scaling is to select a safe and tolerable dose for the first time administration to humans. The approach is based on finding a correlation between the physiological and pharmacokinetic parameters of interest.

The parameters like experimental design, species, analytical errors, and physiochemical properties of drugs such as renal secretion or biliary secretion may have impact on allometric extrapolation. The drawback is that it is essentially empirical and does not allow for differences in metabolic clearance between the species eg: 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 major pathway. An approach for compounds that are actively secreted into the urine has also been proposed although the precise values of some of the physiological scaling factors have been questioned. Unfortunately, when clearance is largely metabolic and low, allometry can significantly over-predict the human value. Recent investigations are addressing this by combining allometric approach with in vitro metabolism data.

A debate on allometric scaling suggested that a great deal of further work is necessary before allometry can be used with confidence in a prospective manner. 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.

Source: PharmaBiz


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