Do changes in Vd have any impact on clinical drug effects?

This will depend entirely on which drug concentration measurements have the greatest impact on drug effects. And here is where our relative ignorance of this particular aspect of drug pharmacology constrains our ability to use PK as a predictor of drug effects.

If for example our understanding of what best predicts drug effects is limited to considerations of 'average' or 'steady-state' drug concentrations, then we are compelled to expect that Vd changes will have little or negligible impact on clinical drug effects. This is because Vd changes do not alter the area-under-the-curve (AUC) of a drug's pharmacokinetics (since AUC is determined primarily by clearance and bioavailability). Remember (F x Dose)/AUC = Clearance?

This line of reasoning has dominated and shaped our thinking for the last few decades as evidenced by the large number of studies looking at clearance or AUC changes as predictors of drug effects. Correspondingly, we have tended to minimize the effect of distributional changes as a predictor.

Is this line of reasoning correct?

Only to a limited extent. We have seen in the previous post, that the immediate and most obvious effect of Vd changes is on the C0. Consequently if a drug's effect is dependent on peak concentrations, Vd changes will have inversely related effects on peak concentrations of the drug profile, and by extension, any clinical effect, be it efficacy or toxicity, associated with the peak.

We see this also with multiple dose regiments.

With a multiple dose regiment, even though changes in Vd are not expected to change the AUC or steady state concentrations, you can see that the fluctuations over the dosage interval are greater if the Vd is smaller (in the above case 115L compared to 230L). With the increased fluctuations, one should note that the peak and trough concentration actually move in different directions, i.e. with a smaller Vd, the peak increases but the trough decreases, while the AUC remains unchanged.

Going back to the original question....do Vd changes have an impact on clinical drug effect? It will depend on whether drug effects relate best to steady-state concentration, the AUC, peak or trough concentrations. And this is poorly understood at the moment.

For the moment however, being over-focused on the AUC therefore limits our ability to see potential causes of variability in drug response.