## What is clinically relevant? [Design Issues]

Dear Helmut:

I believe the spaghetti plots you posted are actually indicative of a infusion of unbound drug.

Release of the encapsulated form follows first order kinetics and is Sequential - kind of like metabolic clearance from parent --> metabolite.

Luckily, you also posted the parent/metabolite curve for doxorubinol. Because of similarity in process, if no free drug is infused, bound and unbound PK should follow the same general shape we see in parent + metabolite.

The fact that total + free dox concentrations are colinear is pretty strong evidence for co-infusion of bound + unbound. Further, the fact that there isn't a lag time in unbound, as well as a nonlinear shape, is evidence, too.

Thanks,
BF