FDA Approval: Serdexmethylphenidate/Dexmethylphenidate for Adult ADHD Treatment


Theresa Cerulli, MD, describes the indication and mechanism of the recent FDA approved combination product serdexmethylphenidate /dexmethylphenidate for the treatment of attention deficit/hyperactivity disorder (ADHD).

Theresa Cerulli, MD: The FDA has recently approved a combination product—the prodrug methylphenidate—and the name is Azstarys. I’m not sure if you’ve had a chance to use it in practice. It’s fairly new.

I’m going to use the brand name Azstarys because it’s a little confusing to clinicians to know what medication I’m talking about if I use the generic names. Azstarys is a combination product made up of 2 ingredients. One is serdexmethylphenidate, a prodrug that’s brand-new, so people haven’t heard of it. The other is a known entity, dexmethylphenidate. I didn’t want people to mix up that those 2 ingredients are combined in 1 medication called Azstarys. If I tried to use the generic, people would think I’m talking about 2 different medications, but I’m not.

I can share some of my clinical experience and a little of what I know about Azstarys.

The approval for Azstarys is for ages 6 years and above. It can be used to treat children, adolescents, and adults. There are 3 dose strengths, and you have the ability to titrate them. They started on the middle dose in the trial, and 93.5% of the kids ended up optimizing on the middle dose or the highest dose in the 6- to 12-year-olds. You have to do 3 dose strengths, but I wanted to point this out in case you’re working with adult patients. Each dose has 2 mg associated with it because you have to represent the milligrams in both the serdexmethylphenidate and the immediate-release dexmethylphenidate portion of the Azstarys. Each dose level has 2 different milligrams listed because it’s a combination drug.

Azstarys is a combination product made up of 70% prodrug and 30% immediate-release dexmethylphenidate. When I say prodrug, 70% of Azstarys is serdexmethylphenidate. It’s a schedule 4, not a schedule 2, prodrug piece, which is very interesting. The other 30% is immediate-release dexmethylphenidate, which is a schedule II substance. Therefore, the entire drug, Azstarys ended up getting classified as a schedule 2 controlled substance, even though 70% of it is schedule 4 serdexmethylphenidate. It’s a novel mechanism, but maybe we can break it down and help people understand.

I’ll start with serdexmethylphenidate, the prodrug portion of Azstarys. It’s an inert substance—that’s what we mean by prodrug—until it’s activated in the body. It has to be bioactivated. That doesn’t happen until it hits the lower GI [gastrointestinal] tract. The serdexmethylphenidate, if you were to snort it or inject it, isn’t activated by other means. That’s what we mean by an inert substance, and that’s why it’s a schedule IV. There are no free amphetamine there until it hits the lower GI tract. The advantage is that it ends up being a very long-acting medication because it’s not activated. The blood levels don’t start coming up on the methylphenidate portion of it until 4 or 5 hours postingestion.

You get this smooth curve toward the end of the day because of the prodrug portion. The beginning of the day is why the 30% immediate-release dexmethylphenidate was built into the Azstarys, because you don’t want to wait 4 to 5 hours for your drug to activate. Some of the immediate release was added as well, 30%. If you look at the combination of the 2 together in the Azstarys, your PK [pharmacokinetic] curve—when the blood levels come up—is within 30 minutes of ingesting the Azstarys. That’s due to some of the immediate-release dexmethylphenidate. If you get this immediate-release portion coming up in the PK curve in your blood levels, and then Azstarys is just starting to come down a little, you’ve got enough from the serdexmethylphenidate, the prodrug portion, to pick up there. There isn’t this biphasic release. It’s up and then there’s a very gradual drop in your dexmethylphenidate levels throughout the 24-hour period.

Anthony Rostain, MD, MA: It’s like an overlap. It’s really nice.

Theresa Cerulli, MD: There are no 2 humps in this PK curve. It’s very fast. It works quickly. When I say works, I know PK curves are blood levels. But that’s where the study is done, which we’ll talk about. The blood levels come up quickly and are sustained. There’s no biphasic PK appearance because of the way the curves overlap. There’s 30% immediate-release dexmethylphenidate and 70% serdexmethylphenidate in the prodrug portion. Azstarys is the curve I just described when you combine those 2.

Transcript edited for clarity

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