Robert L. Findling, MD, MBA, and Timothy Wilens, MD, review serdexmethylphenidate-dexmethylphenidate, a combination agent recently approved for the treatment of ADHD.
Robert L. Findling, MD, MBA: I want to shift gears. At the beginning, we promised folks that we’d talk about a new agent. I wanted us to talk a little about this newly approved combination product. It’s serdexmethylphenidate and dexmethylphenidate. Basically, it’s 70% serdexmethylphenidate and 30% dexmethylphenidate, as far as the active components are concerned. It’s an interesting compound insofar as this is a prodrug and ADHD [attention-deficit/hyperactivity disorder] is very familiar with prodrugs, in which serdexmethylphenidate is a prodrug of dexmethylphenidate.
I’m particularly curious, not just because serdexmethylphenidate is a prodrug but also, interestingly enough, because it’s schedule IV, and dexmethylphenidate and the combination is schedule II. With your background in treating folks with addictions, you’ve got a lot to teach us about it. Start with a little about prodrugs in ADHD, because serdexmethylphenidate isn’t the first of its kind.
Timothy Wilens, MD: That’s exactly right. It’s always nice to see a new entrée. This compound is different insomuch as it’s a prodrug, so it’s a serine linked to dexmethylphenidate in extended-release form. What you get is a serine dexmethylphenidate. Because of the way that combination releases, the way the serine is cleaved in it, it isn’t absorbed into the colon, and it’s down scheduled from a schedule II—what most stimulants are—to a schedule IV, and for good reason. It has lower abuse liability. They studied that. It isn’t new that prodrugs have lower abuse liability. For example, in benzodiazepines—which we aren’t talking about today—there’s good evidence that the extended-release prodrug form has lower abuse liability than others. That’s the one I use for people who have addiction.
To move it back, prodrugs have lower abuse liability, and they were able to demonstrate that. Much to the surprise of a lot of us in the field, they were able to take a stimulant and schedule it as a schedule IV. The last time we had a schedule IV stimulant was years ago with magnesium pemoline, which has long been off the market.
Because of the delayed onset, they add dexmethylphenidate. We have long used dexmethylphenidate, and a lot of people like and use dexmethylphenidate. It’s an isomeric form of methylphenidate, and a lot of people think it’s cleaner on adverse effects—but I’d also say for efficacy—and it gives you a slightly longer effect. You’ve got that combination of an immediate release, so it acts immediately, and then you’ve got this extended-release moiety, which is going to release a bit later; the combination is schedule II-IV. It’s unique because it has both schedules because of the immediate and extended release. We were excited to hear about the prodrug because of its lower abuse liability potential. In their studies, they showed a lower abuse liability compared with immediate-release dexmethylphenidate.
Robert L. Findling, MD, MBA: Let me unpack this a little, because you said a lot of really good stuff. Talk a little about dexmethylphenidate as opposed to racemic dl-methylphenidate. That in and of itself is a bit of a conversation, isn’t it?
Timothy Wilens, MD: It is, and the FDA has asked for what they call isomeric chemistry, which is to purify compounds that have both the right and left—the 2 rotations of molecules. They said that if you can get rid of the left hand, which is typically the less active and has more of the active moiety, it will help with adverse effects and potency. That’s what’s happening. We have existing compounds—both immediate and extended release—that are just dexmethylphenidate. The extended-release form is a 9-hour preparation, so it doesn’t last a long time, but it’s something. We also have that for amphetamine, but we’re focused on methylphenidate. There’s theoretically an advantage
to having just a dextroamphetamine component of methylphenidate.
Robert L. Findling, MD, MBA: I have my own interest in drug metabolism. Do you want to talk a little about the absorption of a prodrug as opposed to a pulsed sustained-release agent? Because they’re certainly different as far as their concentration vs time curves.
Timothy Wilens, MD: Because immediate release or pulse has a release within the first 30 or 45 minutes, which is typical for a lot of the extended release, you’re going to have most of the absorption occurring in the first part of the small intestine through the small intestine with a small amount in the colon. With this compound, you’re getting that release because of the immediate release, but then the bulk of the release is occurring with the serdexmethylphenidate when the serine is cleaved in the colon. You’re having more of a distal absorption of the moiety, which may be part of the reason for the differences between it and other extended-release medicines in terms of liability. That’s less so. It’s more the uptake into the brain. But it’s notable that you have, throughout the GI [gastrointestinal] tract, different absorptions of the different moieties.
Transcript edited for clarity