Serdexmethylphenidate

Identification

Summary

Serdexmethylphenidate is a prodrug of the CNS stimulant dexmethylphenidate used as a first-line treatment for Attention Deficit Hyperactivity Disorder (ADHD).

Brand Names
Azstarys
Generic Name
Serdexmethylphenidate
DrugBank Accession Number
DB16629
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.1,2 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.1,3 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.11,12

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.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 499.52
Monoisotopic: 499.195464906
Chemical Formula
C25H29N3O8
Synonyms
  • Serdexmethylphenidate
External IDs
  • KP-415 inner salt

Pharmacology

Indication

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.11

Pharmacology
Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
Avoid life-threatening adverse drug events
Improve clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events & improve clinical decision support.
Learn more
Pharmacodynamics

Serdexmethylphenidate is a prodrug of the CNS stimulant dexmethylphenidate, which increases extracellular levels of dopamine and norepinephrine in the CNS, leading to altered neurotransmission.3 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.11

Mechanism of action

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.1,2 Proper diagnosis is hindered by a lack of biological markers (based on symptoms alone), a spectrum of severity, and frequent comorbidities such as autism spectrum disorder, reading disabilities, developmental coordination disorders, and tic disorders.1 Although the underlying cause(s) is unclear, dopaminergic, noradrenergic, serotonergic, cholinergic, glutaminergic, and opioid neurotransmission likely plays a role.1,3

Serdexmethylphenidate is a prodrug of the CNS stimulant dexmethylphenidate(MPH), a common first-line treatment for ADHD.11 The main effect of MPH is to increase the extracellular levels of dopamine and norepinephrine, which has numerous potential downstream effects.2,3 This occurs mainly due to MPH's ability to inhibit the corresponding dopamine and norepinephrine monoamine transporters.2,3 Other studies have suggested additional possible MPH functions, including serotonin 5-HT1A receptor agonism,3,4 redistribution of vesicular monoamine transporter-2 (VMAT-2),3,5 and either direct or indirect activation of α2-adrenergic receptors.3,6,7 Overall, imaging studies reveal that MPH acts to alter brain activity in relevant regions associated with executive function, emotional regulation, reward processing, and working memory.3

TargetActionsOrganism
ASodium-dependent dopamine transporter
inhibitor
Humans
ASodium-dependent noradrenaline transporter
inhibitor
Humans
U5-hydroxytryptamine receptor 1A
agonist
Humans
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.11,14 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.11

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.12 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.13

Volume of distribution

Serdexmethylphenidate has a mean apparent volume of distribution of 29.3 L/kg following serdexmethylphenidate/dexmethylphenidate administration.11 Serdexmethylphenidate/dexmethylphenidate (28/6 or 56/12 mg) administered orally in patients aged between six and 17 years of age produced an apparent volume of distribution of dexmethylphenidate of between 37.6 and 66 L/kg.13

Protein binding

Plasma protein binding of serdexmethylphenidate and dexmethylphenidate is low at therapeutic doses, 56% and 47%, respectively, at 5 μM, a concentration roughly 60 times that achieved in therapeutic application.2,11

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 1A1.11,8 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.9,10 Methylphenidate may also be trans-esterified to form ethylphenidate.10

Hover over products below to view reaction partners

Route of elimination

Following oral serdexmethylphenidate dosing in humans, roughly 62% and 37% of the initial dose was recovered in the urine and feces, of which about 0.4% and 11% of the initial dose was recovered unchanged, respectively. Ritalinic acid accounted for approximately 63% of the recovered dose. When methylphenidate was administered orally as a racemate, about 90% of the dose was recovered in urine, of which racemic acid accounted for approximately 80% of the dose.11

Half-life

Following a single oral dose of 52.3 mg/10.4 mg serdexmethylphenidate/dexmethylphenidate, the mean plasma terminal elimination half-lives of each component were roughly 5.7 and 11.7 hours, respectively.11 At steady-state in healthy adults under fasted conditions, serdexmethylphenidate/dexmethylphenidate at 64/8, 56/12, and 48/16 mg resulted in a dexmethylphenidate half-life of between 8.5 ± 2.3 and 9.2 ± 3.5 hours.12

Clearance

Serdexmethylphenidate has a mean apparent clearance of about 3.6 L/h/kg following oral serdexmethylphenidate/dexmethylphenidate administration.11 In patients aged 6-17 years following oral administration of 28/6 or 56/12 mg serdexmethylphenidate/dexmethylphenidate, dexmethylphenidate has a mean apparent clearance of between 2.5 and 3.4 L/h/kg when normalized for dose.13

Adverse Effects
Adverseeffects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.
Learn more
Improve decision support & research outcomes with our structured adverse effects data.
Learn more
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.11

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcebutololThe therapeutic efficacy of Acebutolol can be decreased when used in combination with Serdexmethylphenidate.
AceclofenacThe risk or severity of hypertension can be increased when Aceclofenac is combined with Serdexmethylphenidate.
AcemetacinThe risk or severity of hypertension can be increased when Acemetacin is combined with Serdexmethylphenidate.
Acetylsalicylic acidThe risk or severity of hypertension can be increased when Acetylsalicylic acid is combined with Serdexmethylphenidate.
AlclofenacThe risk or severity of hypertension can be increased when Alclofenac is combined with Serdexmethylphenidate.
AlfentanilThe risk or severity of hypertension can be increased when Alfentanil is combined with Serdexmethylphenidate.
AliskirenThe therapeutic efficacy of Aliskiren can be decreased when used in combination with Serdexmethylphenidate.
AlmotriptanThe risk or severity of hypertension can be increased when Almotriptan is combined with Serdexmethylphenidate.
AmbrisentanThe therapeutic efficacy of Ambrisentan can be decreased when used in combination with Serdexmethylphenidate.
AminophenazoneThe risk or severity of hypertension can be increased when Aminophenazone is combined with Serdexmethylphenidate.
Interactions
Identify potential medication risks
Easily compare up to 40 drugs with our drug interaction checker.
Get severity rating, description, and management advice.
Learn more
Food Interactions
  • Take with or without food. Food does not exert a clinically meaningful effect on dexmethylphenidate exposure, though it does lengthen the time to reach maximum plasma concentration from two hours to approximately 4-4.5 hours.

Products

Products2
Drug product information from 10+ global regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Product Ingredients
IngredientUNIICASInChI Key
Serdexmethylphenidate chlorideFN54BT298Y1996626-30-2GONQEUJYYMYNMN-HWAJWLCKSA-N
Active Moieties
NameKindUNIICASInChI Key
DexmethylphenidateprodrugM32RH9MFGP40431-64-9DUGOZIWVEXMGBE-CHWSQXEVSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
AzstarysSerdexmethylphenidate chloride (52.3 mg/1) + Dexmethylphenidate hydrochloride (10.4 mg/1)CapsuleOralCorium, Inc2021-07-12Not applicableUS flag
AzstarysSerdexmethylphenidate chloride (39.2 mg/1) + Dexmethylphenidate hydrochloride (7.8 mg/1)CapsuleOralCorium, Inc2021-07-12Not applicableUS flag
AzstarysSerdexmethylphenidate chloride (26.1 mg/1) + Dexmethylphenidate hydrochloride (5.2 mg/1)CapsuleOralCorium, Inc2021-07-12Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
0H8KZ470DW
CAS number
1996626-29-9
InChI Key
UBZPNQRBUOBBLN-PWRODBHTSA-N
InChI
InChI=1S/C25H29N3O8/c1-35-24(33)21(17-8-3-2-4-9-17)20-11-5-6-13-28(20)25(34)36-16-27-12-7-10-18(14-27)22(30)26-19(15-29)23(31)32/h2-4,7-10,12,14,19-21,29H,5-6,11,13,15-16H2,1H3,(H-,26,30,31,32)/t19-,20+,21+/m0/s1
IUPAC Name
3-{[(1S)-1-carboxylato-2-hydroxyethyl]carbamoyl}-1-{[(2R)-2-[(1R)-2-methoxy-2-oxo-1-phenylethyl]piperidine-1-carbonyloxy]methyl}pyridin-1-ium
SMILES
[H][C@@]1(CCCCN1C(=O)OC[N+]1=CC=CC(=C1)C(=O)N[C@@H](CO)C([O-])=O)[C@H](C(=O)OC)C1=CC=CC=C1

References

Synthesis Reference

Travis Mickle, Sven M. Guenther, and Gouchen Chi, "Methylphenidate-prodrugs, processes of making and using the same." Patent WO2018107131A1, issued June 14, 2018.

General References
  1. Thapar A, Cooper M: Attention deficit hyperactivity disorder. Lancet. 2016 Mar 19;387(10024):1240-50. doi: 10.1016/S0140-6736(15)00238-X. Epub 2015 Sep 17. [Article]
  2. Childress AC, Komolova M, Sallee FR: An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019 Nov;15(11):937-974. doi: 10.1080/17425255.2019.1675636. Epub 2019 Nov 8. [Article]
  3. Faraone SV: The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev. 2018 Apr;87:255-270. doi: 10.1016/j.neubiorev.2018.02.001. Epub 2018 Feb 8. [Article]
  4. Markowitz JS, DeVane CL, Ramamoorthy S, Zhu HJ: The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT(1A) receptor. Pharmazie. 2009 Feb;64(2):123-5. [Article]
  5. Riddle EL, Hanson GR, Fleckenstein AE: Therapeutic doses of amphetamine and methylphenidate selectively redistribute the vesicular monoamine transporter-2. Eur J Pharmacol. 2007 Sep 24;571(1):25-8. doi: 10.1016/j.ejphar.2007.05.044. Epub 2007 Jun 5. [Article]
  6. Andrews GD, Lavin A: Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors. Neuropsychopharmacology. 2006 Mar;31(3):594-601. doi: 10.1038/sj.npp.1300818. [Article]
  7. Gamo NJ, Wang M, Arnsten AF: Methylphenidate and atomoxetine enhance prefrontal function through alpha2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry. 2010 Oct;49(10):1011-23. doi: 10.1016/j.jaac.2010.06.015. Epub 2010 Sep 1. [Article]
  8. Sun Z, Murry DJ, Sanghani SP, Davis WI, Kedishvili NY, Zou Q, Hurley TD, Bosron WF: Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1. J Pharmacol Exp Ther. 2004 Aug;310(2):469-76. doi: 10.1124/jpet.104.067116. Epub 2004 Apr 13. [Article]
  9. Loureiro-Vieira S, Costa VM, de Lourdes Bastos M, Carvalho F, Capela JP: Methylphenidate effects in the young brain: friend or foe? Int J Dev Neurosci. 2017 Aug;60:34-47. doi: 10.1016/j.ijdevneu.2017.04.002. Epub 2017 Apr 13. [Article]
  10. Markowitz JS, Straughn AB, Patrick KS: Advances in the pharmacotherapy of attention-deficit-hyperactivity disorder: focus on methylphenidate formulations. Pharmacotherapy. 2003 Oct;23(10):1281-99. doi: 10.1592/phco.23.12.1281.32697. [Article]
  11. FDA Approved Drug Products: AZSTARYS (serdexmethylphenidate and dexmethylphenidate) capsules [Link]
  12. KemPharm Poster: Braeckman, et al. (2018) American Professional Society for ADHD and Related Disorders [Link]
  13. KemPharm Poster: Braeckman, et al. (2019) American Professional Society for ADHD and Related Disorders [Link]
  14. KemPharm Poster: Braeckman, et al. poster 2 (2019) American Professional Society for ADHD and Related Disorders [Link]
ChemSpider
81367537
RxNav
2562176
Wikipedia
Serdexmethylphenidate

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAttention Deficit Hyperactivity Disorder (ADHD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10858341No2017-12-092037-12-09US flag
US10954213No2017-12-092037-12-09US flag
US10584112No2017-12-092037-12-09US flag
US9079928No2012-07-272032-07-27US flag
US10584113No2017-12-092037-12-09US flag
US10759778No2017-12-092037-12-09US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP-2.7ChemAxon
pKa (Strongest Acidic)2.56ChemAxon
pKa (Strongest Basic)-2.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area149.18 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity137.75 m3·mol-1ChemAxon
Polarizability50.9 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
This action is mediated by the active moiety dexmethylphenidate following prodrug conversion.
General Function
Monoamine transmembrane transporter activity
Specific Function
Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A3
Uniprot ID
Q01959
Uniprot Name
Sodium-dependent dopamine transporter
Molecular Weight
68494.255 Da
References
  1. Childress AC, Komolova M, Sallee FR: An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019 Nov;15(11):937-974. doi: 10.1080/17425255.2019.1675636. Epub 2019 Nov 8. [Article]
  2. Faraone SV: The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev. 2018 Apr;87:255-270. doi: 10.1016/j.neubiorev.2018.02.001. Epub 2018 Feb 8. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
This action is mediated by the active moiety dexmethylphenidate following prodrug conversion.
General Function
Norepinephrine:sodium symporter activity
Specific Function
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da
References
  1. Childress AC, Komolova M, Sallee FR: An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019 Nov;15(11):937-974. doi: 10.1080/17425255.2019.1675636. Epub 2019 Nov 8. [Article]
  2. Faraone SV: The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev. 2018 Apr;87:255-270. doi: 10.1016/j.neubiorev.2018.02.001. Epub 2018 Feb 8. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
Curator comments
This action is mediated by the active moiety dexmethylphenidate following prodrug conversion. The relevance of 5-HT1A agonism on the pharmacological effects of dexmethylphenidate is not fully understood.
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...
Gene Name
HTR1A
Uniprot ID
P08908
Uniprot Name
5-hydroxytryptamine receptor 1A
Molecular Weight
46106.335 Da
References
  1. Faraone SV: The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev. 2018 Apr;87:255-270. doi: 10.1016/j.neubiorev.2018.02.001. Epub 2018 Feb 8. [Article]
  2. Markowitz JS, DeVane CL, Ramamoorthy S, Zhu HJ: The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT(1A) receptor. Pharmazie. 2009 Feb;64(2):123-5. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Serdexmethylphenidate is hydrolyzed by an unknown enzyme(s) to dexmethylphenidate, which is a substrate for the CES1A1 liver carboxylesterase.
General Function
Carboxylic ester hydrolase activity
Specific Function
Not Available
Gene Name
CES1A1a
Uniprot ID
Q6LAP9
Uniprot Name
Carboxylesterase
Molecular Weight
1908.25 Da
References
  1. Sun Z, Murry DJ, Sanghani SP, Davis WI, Kedishvili NY, Zou Q, Hurley TD, Bosron WF: Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1. J Pharmacol Exp Ther. 2004 Aug;310(2):469-76. doi: 10.1124/jpet.104.067116. Epub 2004 Apr 13. [Article]

Drug created on March 04, 2021 04:54 / Updated on March 09, 2021 02:59