Why isn't the prodrug of methylphenidate (MPH) called lisdexmethylphenidate?

Why the Methylphenidate Prodrug is Called Serdexmethylphenidate, Not Lisdexmethylphenidate

The methylphenidate prodrug is named serdexmethylphenidate because it uses a different chemical moiety (L-serine) attached to d-methylphenidate, whereas lisdexamfetamine uses L-lysine attached to dextroamphetamine—the naming convention reflects the specific amino acid conjugate used in each prodrug's molecular structure. 1

Chemical Structure Determines Nomenclature

• Serdexmethylphenidate is the prodrug of d-methylphenidate that was developed as a new molecular entity and submitted to the FDA in May 2020 1
• The "serdex" prefix indicates the use of L-serine as the amino acid moiety conjugated to the active d-methylphenidate molecule 1
• In contrast, lisdexamfetamine uses L-lysine covalently bonded to dextroamphetamine, hence the "lisdex" prefix 1, 2, 3

Distinct Prodrug Mechanisms

• Both prodrugs require enzymatic hydrolysis after oral ingestion to release their respective active compounds 1, 3
• Lisdexamfetamine undergoes rate-limited hydrolysis by red blood cells to yield d-amphetamine 3, 4
• Serdexmethylphenidate similarly requires enzymatic conversion to release pharmacologically active d-methylphenidate, though the specific hydrolysis mechanism differs due to the serine conjugate 1

Clinical Implications of the Naming

• The FDA considers serdexmethylphenidate a new molecular entity distinct from methylphenidate, just as lisdexamfetamine is distinct from amphetamine 1
• The prodrug mechanism in both cases is designed to provide lower abuse potential due to the requirement for enzymatic conversion before the active stimulant becomes available 1, 3
• The commercial product KP415 combines serdexmethylphenidate with immediate-release d-methylphenidate to provide both early onset and prolonged duration of action 1

Key Distinction from Amphetamine Prodrugs

• The choice of amino acid conjugate (serine vs. lysine) is a deliberate pharmaceutical design decision that affects the pharmacokinetic profile and release characteristics of each prodrug 1, 3
• Using the same naming convention (lisdex-) for both would be chemically inaccurate and misleading, as the molecular structures and potentially the hydrolysis kinetics differ 1, 3