The best method for a two person, or two car at least, trip is to head south from Pen Mar Rd trailhead parking in PA, to the summit of the Blue Ridge (the VA WV line), with a point to point mileage of ~45mi.
The first car needs to be parked at the Pen Mar Rd trailhead, and the second parked at the lot at the corner of US340 & Shenandoah St on the north-west side of the Shenandoah River ~2mi north of the Blue Ridge/VA-WV summit. This means, after the completion of ~45mi south to the Blue Ridge Summit, there is a ~2mi 850ft descent back to the car at US340 & Shenandoah St.
Here's an approximate elevation profile. The mileage is bit off due to the in-capabilities of TOPO! with accounting for actual trail/switchbacks/etc.