Sadly not, at least not via the .NET wrapper (doubt the native C++ DLL will allow it either).
You’re right that it needs to be modified before instantiating (using) the DLL, I’ve not tested it but I doubt the DLL will detect changes to the CFG file when it is in use.
However, you can dispose of the SimConnect object in your own code, then update the CFG file and create a new instance of SimConnect, to force it to reload the CFG settings. Not the nicest approach but it should work, as you’ve effectively reloaded it.
Be careful when attempting this, as the results can be unpredictable, it has the potential to cause memory leaks or even make MSFS unstable.
Dragonlaird