For me there is actually two different problems occurring:
1. The rotating wheels that create lots of turbulence. In all highly aerodynamic vehicles they are fully covered so the wheel "swirls" dont effect the outer surface flow. If we can stop that swirl as close to the wheel the original inside fender volume should not be so big problem. Like regular cars engine bay if you have a grill block is no problem even there is huge volume of air... Same priciples as dampening sounds etc fix the problem as close to where its generated and its easier thing to do.
2. That fender volume which is still open for air flow from specially under the car, underside is not totally smooth, so air can enter that fender at high surface area through the lower suspension arms etc. Wheels turn specially in the front so you cannot block it fully or can you? Of course you can if you are a engineer... Then then outer cover shell which is facing the cars outer surface has quite small clearance to the wheel well that it will not disturb much air flow of the outer car as its "flush" to body
I have looked the interesting aerodynamic car topic almost through and found that Dubonnet Dolphin actually had pretty similar structure.
http://www.autominded.com/3831_1936-dubonnet-dolphin/features#!prettyPhoto[Gallery]/3/
This is what I am shooting for with 20mm gap to tire:
