As Vyvanse goes generic, the first abuse-deterrent methylphenidate has entered the market. Azstarys is the brainchild of Travis Mickle, PhD, who also brought us Vyvanse, and the two share much in common. While Vyvanse locks the prodrug with L-lysine, Azstarys uses a combination lock with the B3 vitamin niacin and the amino acid L-serine. The resulting prodrug is serdexmethylphenidate. Like Vyvanse, it is the more potent dex- version of the stimulant. Beyond that, the similarities end.

For Vyvanse, drug activation takes place in the red blood cells. For serdexmethylphenidate (Azstarys), it occurs in the lower GI tract. Most importantly, activation is much slower with serdexmethylphenidate, with at least a three-hour wait. To overcome this therapeutic delay, Azstarys is front-loaded with 30% instant-release (IR) dexmethylphenidate, allowing onset within 30 minutes. The manufacturer estimates its therapeutic duration at 13 hours, though Azstarys stopped separating from placebo after 10 hours in its singular controlled trial (Kollins SH et al, J Child Adolesc Psychopharmacol 2021;31(9):597–609).

That trial was a three-week classroom study of 149 children aged 6–12 years with ADHD, followed by a larger one-year open-label trial. That is usually not enough for FDA approval, but the agency approved Azstarys in part based on its serum levels, which were close to those of once-a-day dexmethylphenidate IR, at least for the first five hours. Dexmethylphenidate extended release (XR) would provide a more useful comparison. 

The manufacturer suggests that the three dose levels of Azstarys (26.1/5.2, 39.2/7.8, and 52.3/10.4 mg, where the lower number represents IR) are equivalent to dexmethylphenidate XR 20, 30, and 40 mg, respectively. This equivalence is not suggested by the pharmacokinetic data, where dexmethylphenidate XR hovers at serum levels approximately double those of Azstarys over the first eight hours. Head-to-head clinical studies are needed.

What about Azstarys’ misuse potential? Generally, methylphenidates are less rewarding than amphetamines, but this difference is offset by Azstarys’ inclusion of an IR stimulant. Under oral ingestion, Azstarys is about as “liked” as placebo. Unfortunately, those “likes” rise with intranasal insufflation. This is why Azstarys is classified as a Schedule II narcotic even though its prodrug serdexmethylphenidate (which cannot be prescribed alone) falls under the less restrictive Schedule IV classification (along with benzodiazepines). Vyvanse is also a Schedule II drug, although some have suggested it deserves a looser restriction because its rewarding qualities are not changed by intranasal or intravenous delivery and are significantly lower than those of D-amphetamine (Heal DJ et al, Adv Pharmacol 2024;99:251–286).

CARLAT TAKE

Azstarys dampens the potential of stimulant misuse some of the way, but not as much as Vyvanse. Azstarys may not perform as well as dexmethylphenidate XR, particularly in the later half of the day, but head-to-head studies are lacking.