Looking at PK data #1

Here is a set of data, adapted from published information comparing pk data of orally administered Drug X between young subjects and elderly subjects. The data here just provides an opportunity to qualitatively discuss PK effects, and it is not the intention here to 'prove' any PK changes in the elderly.

In this case the most apparent difference is rather large and significant difference in AUC between young and elderly. The AUC in elderly is about 1.84 times greater than that for the young. This is not an unexpected finding. The question is what is the cause of the reduced AUC?

We know from theory that AUC is determined primarily by bioavailability and clearance. However, since we have no way to assess bioavailability here, we shall concentrate on clearance effects instead. The increase in AUC is consistent with a reduction in clearance in the elderly. Again from theory, assuming this is primarily metabolic clearance, we expect that metabolic clearance of an orally administered drug is dependent on protein binding and enzyme activity.

When we inspect the protein binding data we find that the protein binding in elderly is actually increased with the unbound fraction falling from 4.3 to 3.4%. But this magnitude of change is relatively small compared to the estimated change in clearance. Hence it is possible the the total change in clearance reflects both a reduction in unbound fraction as well as a degradation of enzyme activity.

The fall in the unbound fraction potentially also affects the Vd. We have no direct way of assessing the Vd changes here but the Cmax provides indirect (though inaccurate) look at possible Vd changes. The Cmax for the elderly is higher than in the young but marginally less (probably insignificantly less) than the magnitude of change for AUC, so the Vd effect is uncertain.

The halflife changes in the elderly are consistent with the reduction in metabolic clearance.

The uncertainty in this case study is how much any bioavailability changes play in affecting the PK data. The magnitude of halflife change is quite comparable to the magnitude of AUC and clearance changes. This suggests that if there are bioavailability effects it is probably minimal.