Well it certainly should be possible. All the interrupt does is alert you to a status change, and that status change will be reflected in a register somewhere.
I do need every last drop of performance
Can you put some figures to this? What speed are you planning to run I2C? How fast do you need to react? Are you needing to do anything else, other than checking for the incoming data?
whenever I make Peggy run a built-in animation
Animations are typically drawn in something like 25 or 30 FPS. This isn't particularly fast.
I might need that outside the Arduino universe
The universe as you call it isn't particularly an Arduino one. I have stuff running on bare Atmega328 chips. I may use the Arduino IDE to program them, because that is easy. I'm not sure what you mean by that.