Serdexmethylphenidate for ADHD

Serdexmethylphenidate (SDX) is a prodrug of dexmethylphenidate (d-threo-MPH) and is currently only approved in the USA (Azstarys®, KP415 with 70 % SDX and 30 % MPH).¹

The advantage of prodrugs is a slow increase in the active ingredient and a slow decrease in the active ingredient with a prolonged effect, as the conversion from the prodrug delays the release of the active ingredient. See also lisdexamfetamine, which is first converted to dextroamphetamine (Vyvanse).

As the conversion is not sudden, it leads to a prolonged release of dexmethylphenidate, which promises a more uniform and long-lasting effect.
Presumably, some time is needed for the first effects to occur, which is why Serdex methylphenidate is mixed with immediately effective active ingredients.

Serdexmethylphenidate is effective for between 5.7 and 11.7 hours.²
Serdex methylphenidate contains a pyridine ring.²

In the USA, a preparation containing a mixture of serdexmethylphenidate and methylphenidate has been approved for children aged 6 and over and adults with ADHD since 2021:

• Azstarys® (KP415)³⁴
  • Mixture of
    • 70 % serdex methylphenidate (SDX, prodrug of dexmethylphenidate) and
    • 30 % dexmethylphenidate (d-MPH) with immediate release (IR)
  • 26.1/5.2 mg; 39.2/7.8 mg; 52.3/10.4 mg SDX/d-MPH
  • 13 hours working time
  • Approval 2021
  • No food intake required with ingestion, but prolongs effect
  • Degradation of SDX: unknown enzymes
  • Degradation of d-MPH by CES1
  • No interaction with CYP2D6, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2E1 or CYP3A
  • No interaction with alcohol
  • SDX does not prolong the QT interval to a clinically relevant extent

In an open-label study in adults (n = 18, including 4 dropouts), an SDX/d-MPH mixture of 39.2/7.8 mg/day to 52.3/10.4 mg/day showed significant effects on all clinical measures such as the examiners’ symptom scores (AISRS) self-report scores (ASRS), time-dependent ADHD scores (TASS) across the day, impairment scores (CGI), executive function scores (BRIEF-A), and measures of medication uniformity of effect (AMSES). SDX/d-MPH was generally well tolerated.⁵
A study on n = 149 children aged 6 to 12 years with ADHD found an onset of action after 30 minutes and an end of action after 13 hours. The subjects began treatment with 39.2 mg/7.8 mg/day of SDX/d-MPH and received weekly dose adjustments until the optimal dose was reached (maximum dose of 52.3/10.4 mg). During the subsequent 7-day double-blind treatment phase, subjects received their optimal dose of SDX/d-MPH or placebo. Compared to placebo, there was a positive effect from 60 minutes after ingestion until 10 hours after ingestion. Two thirds of the test subjects reported the mild side effects known from MPH, such as difficulty falling asleep and lack of appetite⁶
During one year of treatment, a clinically insignificant slight impairment of growth in height or weight was found in 6- to 12-year-old children. However, children who had not taken the medication for the entire year were also included.⁷
In a multiple-dose study, d-MPH reached steady state before the third daily dose and SDX after the first daily dose.⁸

One study determined the optimal doses in n = 155 children between the ages of 6 and 12 with ADHD.⁹
The starting dose was 39.2/7.8 mg SDX/d-MPH.

• 3.2 % were dosed down to 26.1/5.2 mg
  • ≥ 80% achieved the response threshold of ≥ 50% value improvement on all days
• 39.0 % were up-dosed to 52.3/10.4 mg
  • 72.4 % reached the responder threshold of ≥ 50 % value improvement after 21 days
• 44.5 % remained at 39.2/7.8 mg
  • 81.2 % reached the responder threshold of ≥ 50 % value improvement after 21 days
• the optimal dose was not reported in 3.7% of cases; these were possibly dropouts.

Serdexmethylphenidate affected the sleep of children aged 6 to 12 years with ADHD over the course of 12 months:¹⁰

• improved
  • Parasomnias
  • Daytime tiredness
  • Bedtime resistance
  • Sleep fears
  • waking up at night
• unchanged
  • Sleep duration
  • sleep-related breathing disorders
• deteriorated
  • Delay in falling asleep

Serdexmethylphenidate has a lower abuse potential than d-MPH and phentermine (the latter is only approved in the USA, not in Germany) in terms of intravenous abuse, intranasal abuse and oral use.¹¹