Serdexmethylphenidate

Absorption

Following a single dose of serdexmethylphenidate/dexmethylphenidate (52.3/10.4 mg) compared to extended-release dexmethylphenidate (40 mg) capsules in healthy volunteers under fasted conditions, the Cmax and AUC of dexmethylphenidate were 14.0 ng/mL and 186 ng*h/mL and 28.2 ng/mL and 248 ng*h/mL, respectively. The kinetics are approximately linear over a range of concentrations, with steady-state being reached after the third once-daily dose. Serdexmethylphenidate has a low oral bioavailability of 3%. The Tmax for both serdexmethylphenidate and dexmethylphenidate is approximately two hours under fasted conditions when coadministered. When serdexmethylphenidate is administered as a single entity, the dexmethylphenidate Tmax is approximately eight hours.
Different ratios of serdexmethylphenidate to dexmethylphenidate, 64/8, 56/12, and 48/16 mg, each equivalent to 40 mg of dexmethylphenidate, were tested in healthy adult volunteers under fasted conditions. In each case, dexmethylphenidate reached peak plasma concentrations in roughly two hours (mean between 1.6-1.8 hours), which gradually decreased over 24 hours. The Cmax varied from 15.5 ± 3.7 to 23.8 ± 5.7 ng/mL while the AUC0-24h varied from 187.0 ± 41.0 to 207 ± 54.4 ng*h/mL. Another study investigated the pharmacokinetics of serdexmethylphenidate/dexmethylphenidate (28/6 or 56/12 mg) in patients aged between six and 17 years of age. In general, the Cmax and AUC varied between cohorts and dose but were roughly equivalent when normalized for both dose and body weight.

Toxicity

Serdexmethylphenidate/dexmethylphenidate overdose results in symptoms consistent with CNS overstimulation, including gastrointestinal complaints such as nausea and vomiting, neurological effects including anxiety, euphoria, confusion, and hallucinations/delirium, cardiovascular effects such as arrhythmias, hypertension/hypotension, and tachycardia, general effects such as agitation, restlessness, twitching, convulsions, sweating, flushing, mucous membrane dryness, tachypnea, mydriasis, and serious effects such as rhabdomyolysis, loss of consciousness, coma, and death. Overdose treatment should consist of appropriate symptomatic and supportive care.

The Uses of Serdexmethylphenidate

Serdexmethylphenidate is part of the composition of Azstarys, which consists of a prodrug/drug co-formulation ofserdexmethylphenidate and dexmethylphenidate in a 70:30 molar ratio. Azstarys is approved by the USFDA for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years of age and older. Serdexmethylphenidate consists of pharmacologically active dimethylphenidate attached to the nicotinoyl-L-serine portion via a carboxymethylene linker.

Indications

Serdexmethylphenidate is a prodrug of dexmethylphenidate that is indicated in combination with dexmethylphenidate for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged six years and older.

Background

Attention Deficit Hyperactivity Disorder (ADHD) is an early-onset neurodevelopmental disorder that often extends into adulthood and is characterized by developmentally inappropriate and impaired attention, impulsivity, and motor hyperactivity. The underlying cause of ADHD is unclear but likely involves dysfunction in dopaminergic and noradrenergic neurotransmission, as evidenced by the clear beneficial effect of CNS stimulants such as methylphenidate and amphetamine that increase extracellular dopamine and norepinephrine levels. Serdexmethylphenidate is a prodrug of the CNS stimulant dexmethylphenidate, a common first-line treatment for ADHD, that is combined with dexmethylphenidate to provide extended plasma concentrations and therapeutic benefit with once-daily dosing.
Serdexmethylphenidate was granted FDA approval on March 2, 2021, and is currently marketed as a combination capsule with dexmethylphenidate under the trademark AZSTARYS? by KemPharm, Inc.

Pharmacokinetics

Serdexmethylphenidate is a prodrug of the CNS stimulant dexmethylphenidate, which increases extracellular levels of dopamine and norepinephrine in the CNS, leading to altered neurotransmission. As a CNS stimulant, serdexmethylphenidate carries a risk of abuse, misuse, and dependence, which should be monitored. Also, CNS stimulants are associated with increased blood pressure, heart rate, and risk of serious cardiovascular reactions, including stroke, myocardial infarction, and sudden death; patients should be assessed before starting therapy and monitored for cardiovascular abnormalities. Similarly, CNS stimulants may also result in peripheral vasculopathy, including Raynaud's phenomenon. Due to its ability to alter neurological function, serdexmethylphenidate may exacerbate pre-existing psychoses, induce manic episodes in patients with bipolar disorder, or result in newly diagnosable manic or psychotic symptoms. Frequent, sustained, and painful erections, which may require medical attention, have been observed in patients who have been treated for some time with serdexmethylphenidate, often associated with a dose increase. Finally, like other CNS stimulants, serdexmethylphenidate has been associated with weight loss and growth retardation, which may require treatment interruption in serious cases.

Metabolism

Serdexmethylphenidate is converted to dexmethylphenidate in the lower gastrointestinal tract by as yet unknown enzymes. Following this, dexmethylphenidate is mainly converted to d-α-phenyl-piperidine acetic acid (d-ritalinic acid) in the liver by carboxylesterase 1A1. Other metabolites include the oxidation products 6-oxo-methylphenidate and p-hydroxy-methylphenidate, which are then de-esterified to oxo-ritalinic acid and p-hydroxy-ritalinic acid, respectively. Methylphenidate may also be trans-esterified to form ethylphenidate.

Metabolism

Catabolism of serdexmethylphenidate is believed to occur in the lower gastrointestinal tract. As a result, therapeutic doses of the released dexmethylphenidate do not generally appear until several hours after ingestion. As such, the long-duration action of this prodrug is combined with immediate-release dexmethylphenidate in the marketed combination therapy.