I've put quite a few miles of interstate driving on my P250 and will offer these observations:
Handling and performance at 65 mph (GPS) is comfortable and the bike handles that speed fairly easily and will maintain it on most hills, but not in the mountains. The most I could get out of it going up Saluda Mountain on I-26 was 61. I-77 in WV, between Princeton and Beckley, was much worse, with a maximum speed of 50 in a couple of areas.
Gas mileage is a trade off and is more affected by wind speed and direction than with a larger bike. On a recent long trip (approx. 1,300 miles each way), I got 6 - 8 mpg more on the return leg driving the same roads at the same speeds. Winds were generally from the northwest coming and going and my route was generally northwest going up and southeast coming back. Terrain also makes a bigger difference with the smaller bike. My mileage was unbelievably higher traveling I-40/I-26 coming out of the mountains than it was going up.
A larger bike will deliver about the same gas mileage at 65 as my P250. At 70 or higher, the X500 will probably do better. The trade-off is that at speeds of 60 or below, the smaller engine will walk away from them.
Since I can afford only one bike, I've decided to wear out the one I have and enjoy the gas savings. I usually take only one long interstate trip a year and a couple of shorter ones. The usual suburban errands and back road rides with my buddies are delivering 58-68 mpg, way above what my riding pals are getting on their SW's and B650's. Learning a little patience on the slab can pay off.