I photographed many times with the 645D hand held, and I enjoyed it a lot. Having said that, I do enjoy shooting the 645Z this way a little more, simply because it's more responsive, and the greater range of ISO provides more exposure options in available light. Either way, I wouldn't call it "last resort". If David Burnett could shoot the 2012 Olympics with a 4x5 Speed Graphic hand held, then I guess we can photograph hand held with a Pentax 645 digital rig.
Most of my photography is done on a tripod, but I grew tired of carrying multiple systems awhile ago. I'm slowly divesting everything outside of my Pentax 645 kit. So if I want to shoot indoor candids, street, events, wildlife or whatever else, the Pentax is what I reach for because it's the camera system I want to photograph with, and most often I don't have any other "large" system available. (I do have a Sony pocket camera, and a camera phone.) If you use anything enough, you tend to get good at using it to its maximum potential, within whatever relative strengths & weaknesses it has.
Depending on lens, available light, shooting technique, etc. the D (or Z) may or may not produce the highest resolution / lowest noise images of which the camera is capable. That might be perfectly fine; not all photographs need the highest level of technical quality to achieve the purpose.
Maximum ISO is whatever I need for the exposure I want. Noise tolerance is a personal choice. Though normally I preferred a lower ISO, I shot up to ISO 1600 on the D many times with results usable for what I needed. I try to do more or less the rule of thumb of keeping the shutter speed at or above the reciprocal of the focal length. With the caveat that this rule of thumb is from 35mm full frame equivalent focal lengths, and assumes no stabilization. And the further caveat that sometimes blur, very shallow depth-of-field, or other characteristics are creative choices rather than flaws...