Drug development therapeutic index

All three of these new AmB formulations improve the therapeutic index of the drug considerably compared with Fungizone. Larger cumulative doses can be given, leading to cures that were hitherto impossible. However, they are expensive and thus inaccessible in developing countries where their use would be of most benefit (13). 

In general, bioequivalence is demonstrated if the mean difference between two products is within 20% at the 95% confidence level. This is a statistical requirement, which may require a large number of samples (e.g. volunteers), if the drug exhibits variable absorption and disposition pharmacokinetics. For drugs for which there is a small therapeutic window or low therapeutic index, the 20% limit may be reduced. The preferred test method is an in vivo crossover study and, since this occurs in the development phase, necessitates the emplo)unent of volim-teers. These studies are, therefore, expensive and animal experiments may be substituted, or in vitro experiments if they have been correlated with in vivo studies. 

The role of TDM for different antidepressants varies from being a standard of care issue with TCAs to a discretionary laboratory test with most of the newer drugs. The reason for this difference relates to the pharmacology of the various classes of antidepressants, particularly in terms of toxicity. TDM is essential for the safe use of TCAs because of their narrow therapeutic index and the substantial interindividual differences in elimination rates. These two factors result in the risk that serious toxicity can develop in poor metabolizers on standard doses. In contrast to TCAs, most new antidepressants have such a wide therapeutic index that serious toxicity is not a concern. 

Extrapolations of therapeutic index and toxicity data from animals to humans are reasonably predictive for many but not for all toxicities. Seeking an improved process, a Predictive Safety Testing Consortium of five of America s largest pharmaceutical companies with an advisory role by the Food and Drug Administration (FDA) has been formed to share internally developed laboratory methods to predict the safety of new treatments before they are tested in humans. In 2007, this group presented to the FDA a set of biomarkers for early kidney damage. 

If formulations with three or more release rates are used to develop the IVrVC model, no further evaluation beyond this initial estimation of prediction error may be necessary for non-narrow therapeutic index drugs (Category 2 a and b apphcations, see page 12). However, depending on the results of this internal prediction error calculation, determination of prediction error externally may be appropriate. 

Estimation of Prediction Error Externally. The second aspect relates to how well the model predicts data when one or more additional test data sets are used that differ from those used to define the correlation. This is appropriate in some situations, parhcularly when only two formulations with different release rates are used to develop the IVlVC model, when calculation of prediction error internally is inconclusive, or when a narrow therapeutic index drug is studied. 

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