Valerie, I'm sorry you're confused. Don't know if this will help any. Couple of comments:
Val, I'm curious where you got the information that it took 1 1/2 hours for HC to peak. Do you still have the first article I sent you by these same authors called "Bioavailability of Oral HC?" If so, look at the graph on page 68. It shows what happens with both oral and IV hc in the bloodstream. It looks like it takes about 45 minutes for oral hc to peak, and about 20 minutes for it to peak via IV. Peaking, the way I understand it, is when a drug reaches its maximum level of action. That's not necessarily the same thing as when it starts to have an effect. It probably starts to have some sort of effect shortly after ingestion, not a whole lot maybe, but some. Could you be getting this mixed up with half-life, which IS about 1-1 1/2 hours for IV HC? Half-life has to do with the amount of time it takes for a medication to go down to HALF its previous levels, a slightly different idea.
If you look at the same graph, you'll see what I mean. The highest level of cortisol reached in this example, via IV, is just under 2000 nmol/L. Between an hour to 1 1/2 hrs. later, that same IV dose is down to about half, or a little less than 1000 nmol/L. At about hour 3, it is down to about half again, or ~ 500 nmol/L. And so on, and so forth.
Again, from this graph, it looks like---though a dose of IV vs. oral HC lasts about the same total length of time, ~ 6 hours, in this example---oral hc has a much longer half-life, making the rate at which levels decline, much less steep than the rate at which an IV dose declines. In other words, the drug behaves somewhat differently, when given by injection or taken orally, but they both seem to last about the same length of time. Overall, a more gradual level of decline with the oral dose is probably a good thing and should make trying to figure out how to get optimal coverage with different HC schedules and amounts easier, rather than harder---not that it still isn't QUITE tricky. A LOT of variables to consider. But, again, Laura K. would be a much better person to ask about the specifics of this, as she's actually been busy working out the details, while I'm merely yakking.
As far as why they said 4 AM, rather than 3 AM, I think it's probably because, from the looks of the cortisol chart, levels do start to rise ~3, but it looks like momentum doesn't really start to pick up until a little bit later. It's probably 6 of 1, 1/2 dozen of the other, if 3AM or 4AM is more defensible. It would probably depend somewhat on if one gave the next dose at 6 AM, or 7 AM (in order to address the BIGGEST problem, which is at 8 AM) and what the size of that dose is. Though I understand what prompted you to move the dose from 3 to 2, I'm not sure I would agree that that would be the thing to do. By moving it back towards an earlier time, you're moving the dose away from when levels start to rise. If you move it forward, you would be moving it towards when the levels start to rise, which I think would be the goal. In that way, it makes more sense to me the way it states in the paper, which is to move it up (towards 4 AM) rather than back (towards 2 AM.)
If you relook at the Moeller study, you'll see that they gave the last dose at 5:30 PM, rather than 4 PM. Going by the letter of the law, those might be different times than the Charmandari article, but the basic idea is still the same. I guess that is what I would like to stress here, more than anything, in response to Julia's original question. It's the concept of dosing when ACTH levels are highest, that is the goal here. And the basic thing to remember is that ACTH slowly starts to rise ~3 AM, PEAKS sharply at ~ 8 AM, then gradually declines for the rest of the day, reaching the lowest levels at nighttime. To be optimally efficient, dosing times should try to mimic that idea, as much as possible. As long as the concept is still the same, the specific hour--I think--is secondary.