Thanks for the input, folks. I was crunching some numbers for a new campaign I'm just starting, and I came up with the following:
MDT = (Con score + base Fort bonus - size modifier), min. 1.
Thus, smaller creatures get a penalty, while big ones get a few extra points.
Now, this might seem exorbitantly high, but it's actually a D&D campaign (not Modern), and high-CR creatures can whap out a *lot* of damage: I'm thinking the MDT check, then, will be a Fort save (DC 10 + 1/2 total damage taken).
So, for instance, a 10th-level human fighter with a 14 Con has an MDT of 21 and a Fort save of +10 (assuming a +1 bonus of some kind on Fort saves); if he takes 21 p.o.d. from an attack, he must make a DC 20 (= 10 base + 1/2 of 21) Fort save (thus, having a 50% chance of success). (Sure makes Great Fortitude and the like a lot more valuable...).
Does that math seem reasonable?