Advances in the Management of ADHD in Adult Population - Episode 14
Drs Cerulli and Cutler discuss the data and pharmacological properties of amphetamine XR oral tablets.
Andrew Cutler, MD: These newer technologies provide much less intraindividual variability or consistency from day to day. They seem to have much more favorable pharmacokinetics [PK] as far as less of that sharp up, sharp down, or peak-to-trough ratio, and that more gradual descent.
One other thing I’d like to add that people don’t talk about a lot with amphetamines is in my experience, some people need a little L. Back in the 1970s and 1980s, we took the D train, where we went to all D-amphetamine. It was thought that the D isomer carried all the efficacy and L wasn’t that effective. That absolutely isn’t true. D and L are both active, at least for amphetamines. They just do different things. The D happens to be more effective for what they were looking for at the time: hyperactivity. As Michael knows, this was called hyperkinetic reaction of childhood at one point, and then of course minimal brain dysfunction—we won’t go there. For a lot of people, with lisdexamfetamine being only the D isomer, I find that some people need the L. They do better with a racemic mixture. What I like about the tablet and the liquid that we’re talking about is they mirror the mixed amphetamine salt 3 parts D to 1 part L.
Theresa R. Cerulli, MD: Dr Cutler, give some information on the pharmacokinetics of both the amphetamine XR [extended-release] oral suspension and the tablets—the 2 formulations—because it can be confusing. Perhaps you can elaborate on that and some of the efficacy and safety data.
Andrew Cutler, MD: As you know, I was an investigator on the pivotal trial that got the tablet approved. I had about 40 patients at my site on this medication. We used an interesting design that’s usually used in the pediatric trials. This was a laboratory classroom design where we brought people into the clinic early in the morning and we did certain ratings. They did math problems and other things. We did that before they took the medicine and then at various times after they took the medicine, going throughout a whole 13- or 14-hour day. We saw rapid onset of efficacy within the first half hour that extended throughout a 13-hour day.
The magic of how you can do this is the LiquiXR technology we’ve been talking about, which is achieved through tiny resin particles and an ion exchange process that separates the amphetamine from the salt. It could be amphetamine hydrochloride or amphetamine sulfate. You get rid of the anion portion in a liquid ion exchange system, and you bind the base amphetamine to these resin particles. Then they’re overcoated. Some of them are immediate release. Some of them are overcoated. There’s an infinite number of thicknesses of coating, which is so incredible, so that when you’re swallowing this and they’re traversing through the GI [gastrointestinal] tract, there’s an ion exchange process that happens as cations from your gastric fluid have to diffuse through the coating. Then they do an exchange with the amphetamine base. Then that has to diffuse back through that coating again to get out into the gut and be absorbed. You can imagine millions of different thicknesses. You get this real gradual release.
If we compare that with the other amphetamine delivery systems, they’re much less continuous in the release. With the mixed amphetamine salt XR, the original was 2 beads. That was meant to mimic twice-a-day dosing. You had an immediate release bead, a peak, and then an extended-release bead kicked in later. The peak came down and then back up again with a sharp drop.
The lisdexamfetamine prodrug should give you extended-release technology. But if you look at the actual PK curve in the package insert, there’s a lot of up and down to that. That has been my experience with lisdexamfetamine. It doesn’t always last long enough. I’m often giving a booster later in the day. I have a lot of the wearing off, the crash with that on the back end. With this new LiquiXR technology preparation, I get what I’m looking for: the early onset, the smooth day, and the gradual decrease on the back end.
Theresa R. Cerulli, MD: Smooth curves, smooth day.
Andrew Cutler, MD: Yes. Viloxazine XR has also been a real game-changer in some ways. Birgit mentioned one property is the fact that it’s the only nonstimulant that I can give to someone who can’t or won’t swallow pills, because it’s a capsule with beads you can sprinkle.
The other thing is the mechanism of action. Viloxazine was available for many years in Europe as an effective antidepressant, as opposed to atomoxetine [Strattera], which was originally developed to be an antidepressant and failed. Right away, we know there’s something different, even though the package insert for both says norepinephrine reuptake inhibitor. We’ve learned that viloxazine also binds to at least 3 serotonin receptors: 5-HT2B, 5-HT2C, and 5-HT7. That perhaps gives it some efficacy for depression and anxiety, and maybe helps augment the norepinephrine reuptake inhibition. I’m thinking about this medicine for adults who have that comorbidity, or even children who I want to treat with a nonstimulant. Both of these medicines were approved in the past year and have been significant additions to our armamentarium.
Theresa R. Cerulli, MD: They’ve really added something in terms of the unmet treatment needs that we’ve looked forward to having. I wanted to clarify that the viloxazine that was available in Europe and approved for use in depression was immediate-release viloxazine.
Andrew Cutler, MD: That’s right. It was the immediate release. You had to take it 3 times a day.
Theresa R. Cerulli, MD: It wasn’t that it didn’t work as an antidepressant, it was just challenging to take 3 times a day. When it was brought to the US in the extended-release form, it wasn’t tested for depression here. It was tested for and has been approved for treating ADHD [attention-deficit/hyperactivity disorder] as a nonstimulant.
Andrew Cutler, MD: It’s once a day now here.
Theresa R. Cerulli, MD: The brand for viloxazine XR is Qelbree, which didn’t exist in Europe. They just had the immediate-release viloxazine. It gets very confusing with the names. We have thrown out so many today. I wanted to be clear regarding which medication we’re talking about.
Transcript edited for clarity