Practice Pearl 4: Calculating Doses for Individualized Treatment
The panel provides an explanation on the appropriate dose calculation for factor VIII.
Luigi Brunetti, PharmD, MPH: That leads us to our last item in terms of dosing. Of course, we want to make sure we have the right dose of medication for our patients to reduce that bleeding risk. For factor VIII products, is there a typical dosage recommendation or dosage calculator?
Robert F. Sidonio, Jr, MD: I'm going to let you start with that.
Giles Slocum, PharmD: Yes, there is a typical dose that we think of. So 0.5 U/kg is traditionally thought to bring the factor VIII level up by 1%. Another way to say that is if you were at 0% and you needed to get 100%, 50 U/kg is a pretty solid dose with most pharmacokinetics [PK] in recovery that we've seen in our patient population. So standard dose calculator-wise, I would probably refer to that 0.5 U/kg, 1% increase.
Robert F. Sidonio, Jr, MD: You see that across most age groups with factor VIII. For factor IX there's a difference in incremental recovery. But generally, for standard and most extended half-life products, if you're giving 50 U/kg, that's the easiest way to achieve 100%. And if somebody has 1% or 2%, we don't really worry too much about that because that's a pretty trivial number.
But it's also important for us to check that peak: we call it a peak. We often will do that in our clinic as we're doing inhibitor surveillance because that may be a clue that something is going on. We'll give an infusion in clinic when we're getting their laboratory tests. Then we check a level 15 to 30 minutes later. And then sometimes we try to time it such that we see what their trough is. That's the level immediately prior to their next dose. Because remember, as we talked about, we're trying to keep their factor VIII levels above 1%. And if we see it drifting below there, we may need to adjust the dose up. And in children, they seem to metabolize factor VIII much quicker, their half-life is less. Their peak is generally similar, but they definitely don't hold on to actor VIII like an adult. And so we often will track that because we want to know what their dose is, if they call us for a bleeding event.
Luigi Brunetti, PharmD, MPH: I didn’t disclose this to you earlier, but my big interest is pharmacokinetics. To me, this is an area where I think we can use these pharmacokinetic principles to enhance dosing. And in fact, we do see heterogeneity in the clearance especially of these products for whatever reason. There are some theories behind why. In some patients it may be of value to do these pharmacokinetic studies so we can individualize the dose. Now the other item is controversial, but hey, that would make our discussion interesting.
Robert F. Sidonio, Jr, MD: Yes, sure.
Luigi Brunetti, PharmD, MPH: What do you do in the obese patient who requires factor VIII?
Giles Slocum, PharmD: Yes, that is a tough question. I was actually going to try to spin that on you after your disclosure. This is something we think about for even our emergent reversal of anticoagulants with some of the factor VIII products and in that specific population.
There is debate out there, the idea of circulating blood volume where we would see that this factor VIII product might require a smaller dose. We don’t dose adjust currently. One of our hemophilia care providers that I had a discussion with had a study where they looked at these preliminary type data, and we didn’t really see a big difference between the obese population and our normal weights, if you will. I’m curious what you guys do in Atlanta.
Robert F. Sidonio, Jr, MD: In children, we try to start with a dose that we would based on their weight. For our obese patients, we seem to see that it can accumulate the level. It was interesting, there was a study done years ago in which they took a couple of clinical trial data and they took some of the pharmacokinetics, and they looked at it. And it’s always hard because in clinical trials they tend to get mostly ideal body weight. They eliminate most of the morbidly obese patients. But in hemophilia A, what they saw is that the recovery got better as the weight went up into the BMIs [body mass indexes] of 30 up to 35. And that makes sense.
So the incremental recovery was better. And so you could theoretically dose less on those patients, or maybe at least round down on the vial sizes. This goes back to the personalization. We have all these new instruments, and I really wish they had these earlier because we have all these new non-factor VIII products coming, which will not require any of these calculators. But, for example, WAPPS-Hemo treatment center network is a big dose calculator that we’re using in which you can do population kinetics, and you can do limited time points because, as you know, if you did a full PK curve, you might need 7 to 10 time points. And that’s challenging to ask a child to come in and say, “Hey, let’s give you an infusion, let’s check this. For the next 8 hours you’ve got to stay here, and you need to come back tomorrow and get 3 or 4 more time points.”
And so this helps us calculate that better. We can dose adjust, which I think is good because we could obviously potentially save money with those patients. And you always worry about, as those patients get older, you really don’t want them to have peaks of 180 IU dL−1. Or maybe it will accumulate if they’re bleeding and they’re getting really high doses; they could get into trouble, particularly if they have a central line. And so we haven’t made a plan but definitely, when we’ve noticed the patients are obese, we look a little closer and we think about dose reducing as needed, particularly if it gets to really, really high peaks.
Luigi Brunetti, PharmD, MPH: In the manufacturing information, they all recommend actual body weight for the dosing of the factor VIII products. There are a couple of papers that show exactly that, if you use an ideal body weight to dose, you may save product, reducing costs, but we don’t have a ton of data in terms of outcomes yet.
Robert F. Sidonio, Jr, MD: The outcome data, right.
Luigi Brunetti, PharmD, MPH: The bottom line though is, as you said, individualization, right? I think that would be the opportunity where we can individualize the dose. But we need some PK sampling. If we are going to do it, you don’t want to do the traditional 7 to 10 time points. You can probably get away with 3 or 4 time points and get some pretty useful data to individualize the patient dose.
And then finally in terms of obesity—and this is the last thing I’ll bring up on this—it does put more strain on the joints. That’s something to think about as well, maybe they do need a little bit more.
Robert F. Sidonio, Jr, MD: They might need more aggressive prophylaxis because of it. And that’s the importance of having an HTC [hemophilia treatment center] and having those difficult conversations about being active because some of those older patients were told they shouldn’t do any physical activity, so we shouldn’t be too shocked that they’re obese adults. And so now, there’s a really big focus on strengthening your joints. It’s OK for patients to run, to participate in aerobic activity, and so hopefully we don’t see as much of that in the future.