Solriamfetol

Solriamfetol
Clinical data
Trade namesSunosi
Other namesSKL-N05, ADX-N05, ARL-N05, YKP10A, R228060, and JZP-110; (R)-2-amino-3-phenylpropylcarbamate hydrochloride
AHFS/Drugs.comMonograph
MedlinePlusa619040
License data
Routes of
administration		By mouth[1]
Drug classNorepinephrine–dopamine reuptake inhibitors; Wakefulness-promoting agents; Psychostimulants
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~95%[1]
Protein binding13.3–19.4%[1]
MetabolismMinimal (~1%)[1]
Metabolites• N-Acetylsolriamfetol (~1%)[1]
Elimination half-life~7.1 hours[1]
ExcretionUrine (95% unchanged)
Identifiers
  • (2R)-2-Amino-3-phenylpropyl carbamate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC10H14N2O2
Molar mass194.234 g·mol−1
3D model (JSmol)
  • C1=CC=C(C=C1)C[C@H](COC(=O)N)N
  • InChI=1S/C10H14N2O2/c11-9(7-14-10(12)13)6-8-4-2-1-3-5-8/h1-5,9H,6-7,11H2,(H2,12,13)/t9-/m1/s1
  • Key:UCTRAOBQFUDCSR-SECBINFHSA-N

Solriamfetol, sold under the brand name Sunosi, is a wakefulness-promoting medication used in the treatment of excessive sleepiness related to narcolepsy and sleep apnea.[1][5][6] It is taken by mouth.[1]

Common side effects of solriamfetol include headache, nausea, anxiety, and trouble sleeping.[1] It is a norepinephrine–dopamine reuptake inhibitor (NDRI) and is thought to work by increasing levels of the neurotransmitters norepinephrine and dopamine in the brain.[1][5] Solriamfetol has also been found to act as a TAAR1 agonist, an action that may also be involved in its effects.[7]

The drug was discovered by a subsidiary of SK Group, which licensed rights outside of eleven countries in Asia to Aerial Pharma in 2011.[8] In addition to its approved indication of excessive sleepiness, solriamfetol is under development for certain other uses including the treatment of attention deficit hyperactivity disorder (ADHD), binge eating disorder, and circadian rhythm sleep disorders.[9]

Medical uses

Solriamfetol is used to promote wakefulness in the treatment of excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea in adults.[1] It appears to be more effective in improving excessive daytime sleepiness associated with obstructive sleep apnea than certain other wakefulness-promoting agents including modafinil, armodafinil, and pitolisant.[10]

Available forms

Solriamfetol is available in the form of 75 and 150 mg oral tablets.[1]

Side effects

Side effects of solriamfetol include headache, nausea, decreased appetite, insomnia, anxiety, irritability, feeling jittery, dizziness, chest discomfort, heart palpitations, dry mouth, increased sweating, abdominal pain, constipation, and diarrhea.[1]

Misuse potential

Solriamfetol at higher-than-approved doses—specifically doses of 300, 600, and 1,200 mg, which are 2 to 4 times the maximum recommended dose—produces drug-liking responses, including elevated mood and feelings of relaxation, that are similar in degree to those of phentermine (a Schedule IV controlled substance).[1] Elevated mood occurred in 2.4% with placebo, 8 to 24% with solriamfetol, and 10 to 18% with phentermine, while feelings of relaxation occurred in 5% with placebo, 5 to 19% with solriamfetol, and 15 to 20% with phentermine.[1] As such, solriamfetol has significant misuse potential and is a controlled substance in the United States.[1] However, solriamfetol showed less misuse potential than Schedule II controlled stimulants like amphetamine and cocaine.[11] Consequently, the misuse potential of solriamfetol was rated as low and it was placed in the Schedule IV controlled substance category alongside phentermine.[11]

Pharmacology

Pharmacodynamics

Solriamfetol is a norepinephrine–dopamine reuptake inhibitor (NDRI).[1] It binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET) with affinities (Ki) of 14.2 μM and 3.7 μM, respectively.[1] It inhibits the reuptake of dopamine and norepinephrine with IC50 values of 2.9 μM and 4.4 μM, respectively.[1] It has weak affinity for the serotonin transporter (Ki = 81.5 μM) and does not appreciably inhibit serotonin reuptake (IC50 > 100 μM).[1] In addition to its dopamine and norepinephrine reuptake inhibition, solriamfetol has been found to act as an agonist of the human and rodent TAAR1 (EC50 = 10–16 μM) at clinically relevant concentrations similar to those of its DAT and NET inhibition.[7] Solriamfetol has no appreciable affinity for a variety of other targets, including the dopamine, serotonin, adrenergic, GABA, adenosine, histamine, orexin, benzodiazepine, and acetylcholine receptors.[1]

Pharmacokinetics

The oral bioavailability of solriamfetol is approximately 95%.[1] The median time to peak levels of solriamfetol is 2 hours, with a range of 1.25 to 3.0 hours.[1] A high-fat meal has minimal influence on the peak and total concentrations of solriamfetol, but does delay time to peak levels by approximately 1 hour.[1] The apparent volume of distribution of solriamfetol is approximately 199 L.[1] The plasma protein binding of solriamfetol is 13.3% to 19.4% over a concentration range of 0.059 to 10.1 μg/mL.[1] Solriamfetol is minimally metabolized in humans.[1] It shows first-order elimination with oral administration and has an elimination half-life of about 7.1 hours.[1] The half-life of solriamfetol increases in the context of renal impairment.[1] Approximately 95% of a dose of solriamfetol is eliminated in urine as unchanged solriamfetol and 1% or less is eliminated as the minor inactive metabolite N-acetylsolriamfetol.[1]

Chemistry

Solriamfetol is a substituted phenethylamine derived from d-phenylalanine.[12] Its chemical name is (R)-2-amino-3-phenylpropylcarbamate.[12]

History

The drug was discovered by a subsidiary of SK Group, which licensed rights outside of eleven countries in Asia to Aerial Pharma in 2011.[8] Aerial ran two Phase II trials of the drug in narcolepsy[13] before selling the license to solriamfetol to Jazz in 2014; Jazz Pharmaceuticals paid Aerial $125 million up front and will pay Aerial and SK up to $272 million in milestone payments, and will pay double-digit royalties to SK.[8][14]

In 2019, solriamfetol was approved in the United States to improve wakefulness in adults with narcolepsy or obstructive sleep apnea (OSA).[15][16] It was granted orphan drug designation.[17]

The U.S. Food and Drug Administration (FDA) approved solriamfetol based primarily on evidence from five clinical trials (Trial 1/NCT02348593, Trial 2/NCT02348606, Trial 3/NCT02348619, Trial 4/NCT02348632, Trial 5 NCT01681121) of 622 patients with narcolepsy or obstructive sleep apnea (OSA).[15] The trials were conducted in Canada, Europe, and the United States.[15]

Solriamfetol was approved for medical use in the European Union in January 2020.[4]

In March 2022, it was announced that Axsome Therapeutics would be acquiring Solriamfetol, under the brand name Sunosi, from Jazz Pharmaceuticals, for an upfront sum of $53 million. Jazz will receive a high single-digit royalty on Axsome's U.S. net sales of Sunosi in the current indication, and a mid-single-digit royalty in the future indications. Axsome will also assume the commitments of Jazz to SK Biopharmaceuticals and Aerial Biopharma.[18]

Society and culture

Names

During development it has been called SKL-N05, ADX-N05, ARL-N05, and JZP-110.[9]

In the United States, solriamfetol is a Schedule IV controlled substance,[1] meaning that it has an accepted medical use and a low potential for abuse, but that abuse may lead to physical or psychological dependence.[19] A prescription is required, and can only be refilled up to five times in a six-month period.[20] In countries of the European Union, a prescription is required.[4]

Research

Solriamfetol is under development for the treatment of attention deficit hyperactivity disorder (ADHD), binge eating disorder, and circadian rhythm sleep disorders.[9][21] As of September 2023, it is in phase 3 clinical trials for ADHD and phase 2 clinical trials for binge eating disorder and circadian rhythm sleep disorders.[9][21] A case report of solriamfetol for the treatment of ADHD has been published.[22] Solriamfetol was also under development for the treatment of depressive disorders, but development for this indication was discontinued.[9] In May 2024, the National Institutes of Health (NIH) announced a trial of solriamfetol for the treatment of long COVID.[23]

References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af "Sunosi – solriamfetol tablet, film coated". DailyMed. 16 October 2019. Retrieved 24 November 2019.
  2. ^ "Summary Basis of Decision (SBD) for Sunosi". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  3. ^ "Health product highlights 2021: Annexes of products approved in 2021". Health Canada. 3 August 2022. Retrieved 25 March 2024.
  4. ^ a b c "Sunosi EPAR". European Medicines Agency (EMA). 12 November 2019. Retrieved 26 September 2020.
  5. ^ a b Powell J, Piszczatoski C, Garland S (October 2020). "Solriamfetol for Excessive Sleepiness in Narcolepsy and Obstructive Sleep Apnea". Ann Pharmacother. 54 (10): 1016–1020. doi:10.1177/1060028020915537. PMID 32270686. S2CID 215605290.
  6. ^ Abad VC, Guilleminault C (December 2018). "Solriamfetol for the treatment of daytime sleepiness in obstructive sleep apnea". Expert Rev Respir Med. 12 (12): 1007–1019. doi:10.1080/17476348.2018.1541742. PMID 30365900. S2CID 53106520.
  7. ^ a b Gursahani H, Jolas T, Martin M, Cotier S, Hughes S, Macfadden W, et al. (2023). "Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion". CNS Spectrums. 28 (2): 222. doi:10.1017/S1092852923001396. ISSN 1092-8529. In vitro functional studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 μM) were within the clinically observed therapeutic solriamfetol plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. TAAR1 agonist activity was unique to solriamfetol; neither the WPA modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity.
  8. ^ a b c Ji-young S (5 March 2018). "SK Biopharmaceuticals' narcolepsy drug on track to hitting US market". The Korea Herald.
  9. ^ a b c d e "Solriamfetol – Jazz Pharmaceuticals/SK Biopharmaceuticals". AdisInsight. Retrieved 13 October 2023.
  10. ^ Pitre T, Mah J, Roberts S, Desai K, Gu Y, Ryan C, et al. (May 2023). "Comparative Efficacy and Safety of Wakefulness-Promoting Agents for Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea : A Systematic Review and Network Meta-analysis". Ann Intern Med. 176 (5): 676–684. doi:10.7326/M22-3473. PMID 37155992. S2CID 258558603.
  11. ^ a b "Federal Register :: Request Access". 17 June 2019.
  12. ^ a b Abad VC, Guilleminault C (2017). "New developments in the management of narcolepsy". Nature and Science of Sleep. 9: 39–57. doi:10.2147/NSS.S103467. PMC 5344488. PMID 28424564.
  13. ^ Sullivan SS, Guilleminault C (2015). "Emerging drugs for common conditions of sleepiness: obstructive sleep apnea and narcolepsy". Expert Opinion on Emerging Drugs. 20 (4): 571–82. doi:10.1517/14728214.2015.1115480. PMID 26558298. S2CID 7951307.
  14. ^ Garde D (14 January 2014). "Jazz bets up to $397M on Aerial's narcolepsy drug". FierceBiotech.
  15. ^ a b c "Drug Trials Snapshots: Sunosi". U.S. Food and Drug Administration (FDA). 16 April 2019. Archived from the original on 28 September 2019. Retrieved 24 November 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  16. ^ "Drug Approval Package: Sunosi". U.S. Food and Drug Administration (FDA). 29 April 2019. Retrieved 24 November 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  17. ^ "Solriamfetol Orphan Drug Approval". U.S. Food and Drug Administration (FDA). Retrieved 24 November 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  18. ^ "Axsome To Buy Sunosi From Jazz". NASDAQ. Retrieved 28 March 2022.
  19. ^ 21 U.S.C. § 812 – Schedules of controlled substances
  20. ^ "Manuals – Practitioner's Manual – Section V". Archived from the original on 7 January 2014. Retrieved 30 May 2021. Retrieved 2014-01-07
  21. ^ a b Surman CB, Walsh DM, Horick N, DiSalvo M, Vater CH, Kaufman D (October 2023). "Solriamfetol for Attention-Deficit/Hyperactivity Disorder in Adults: A Double-Blind Placebo-Controlled Pilot Study". J Clin Psychiatry. 84 (6). doi:10.4088/JCP.23m14934. PMID 37819836. S2CID 263715808.
  22. ^ Naguy A, El-Sheshaie A, Elsori DH, Alamiri B (April 2021). "Solriamfetol for attention deficit hyperactivity disorder". CNS Spectr. 27 (6): 662–663. doi:10.1017/S1092852921000328. PMID 33870884.
  23. ^ "NIH to open long COVID clinical trials to study sleep disturbances, exercise intolerance, and post exertional malaise". National Institutes of Health (NIH). 7 May 2024. Retrieved 2 August 2024.