Droxidopa

Droxidopa (INN; trade name Northera; also known as L-DOPS, L-threo-dihydroxyphenylserine, L-threo-DOPS and SM-5688) is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitter norepinephrine (noradrenaline).[1] Unlike norepinephrine, droxidopa is capable of crossing the protective blood–brain barrier (BBB).[1]

Droxidopa
Clinical data
Trade namesNorthera
Other namesβ,3-Dihydroxytyrosine
AHFS/Drugs.comMonograph
MedlinePlusa614025
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability90%
MetabolismLiver
Elimination half-life1.5 hours
ExcretionKidney
Identifiers
  • (2S,3R)-2-Amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.215.254
Chemical and physical data
FormulaC9H11NO5
Molar mass213.189 g·mol−1
3D model (JSmol)
  • N[C@H](C(=O)O)[C@H](O)c1ccc(O)c(O)c1
  • InChI=1S/C9H11NO5/c10-7(9(14)15)8(13)4-1-2-5(11)6(12)3-4/h1-3,7-8,11-13H,10H2,(H,14,15)/t7-,8+/m0/s1
  • Key:QXWYKJLNLSIPIN-JGVFFNPUSA-Na
  (verify)

Medical uses

Side effects

With over 20 years on the market, droxidopa has proven to have few side effects of which most are mild. The most common side effects reported in clinical trials include headache, dizziness, nausea, hypertension and fatigue.[5][6][7]

Pharmacology

Droxidopa is a prodrug of norepinephrine used to increase the concentrations of these neurotransmitters in the body and brain.[1] It is metabolized by aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Patients with NOH have depleted levels of norepinephrine which leads to decreased blood pressure or hypotension upon orthostatic challenge.[8] Droxidopa works by increasing the levels of norepinephrine in the peripheral nervous system (PNS), thus enabling the body to maintain blood flow upon and while standing.[8]

Droxidopa can also cross the blood–brain barrier (BBB) where it is converted to norepinephrine from within the brain.[1] Increased levels of norepinephrine in the central nervous system (CNS) may be beneficial to patients in a wide range of indications. Droxidopa can be coupled with a peripheral aromatic L-amino acid decarboxylase inhibitor (AAADI) or DOPA decarboxylase inhibitor (DDC) such as carbidopa (Lodosyn) to increase central norepinephrine concentrations while minimizing increases of peripheral levels.

Chemistry

Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS), is chemically analogous to levodopa (L-3,4-dihydroxyphenylalanine; L-DOPA). Whereas levodopa functions as a precursor and prodrug to dopamine, droxidopa is a precursor and prodrug of norepinephrine.

History

Droxidopa was developed by Sumitomo Pharmaceuticals for the treatment of hypotension, including NOH,[2] and NOH associated with various disorders such as MSA, FAP, and PD, as well as IDH. The drug has been used in Japan and some surrounding Asian areas for these indications since 1989. Following a merger with Dainippon Pharmaceuticals in 2006, Dainippon Sumitomo Pharma licensed droxidopa to Chelsea Therapeutics to develop and market it worldwide except in Japan, Korea, China, and Taiwan. In February 2014, the Food and Drug Administration approved droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension.[9]

Clinical trials

A systematic review and meta-analysis conducted on clinical trials comparing the clinical use of droxidopa and midodrine have found that midodrine was more likely to cause supine hypertension than droxidopa in patients with NOH. Midodrine was also found to be slightly more effective at raising blood pressure but not statistically significantly so.[10]

Chelsea Therapeutics obtained orphan drug status (ODS) for droxidopa in the US for NOH, and that of which associated with PD, PAF, and MSA. In 2014, Chelsea Therapeutics was acquired by Lundbeck along with the rights to droxidopa which was launched in the US in Sept 2014.[11]

Research

Droxidopa alone and in combination with carbidopa has been studied in the treatment of attention deficit hyperactivity disorder (ADHD).[12][13]

References
  1. Goldstein DS (2006). "L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug". Cardiovascular Drug Reviews. 24 (3–4): 189–203. doi:10.1111/j.1527-3466.2006.00189.x. PMID 17214596.
  2. Mathias CJ (March 2008). "L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience". Clinical Autonomic Research. 18 (Supplement 1): 25–29. doi:10.1007/s10286-007-1005-z. PMID 18368304. S2CID 29861644.
  3. Calandra-Buonaura G, Doria A, Lopane G, Guaraldi P, Capellari S, Martinelli P, et al. (February 2016). "Pharmacodynamics of a low subacute levodopa dose helps distinguish between multiple system atrophy with predominant Parkinsonism and Parkinson's disease". Journal of Neurology. 263 (2): 250–256. doi:10.1007/s00415-015-7961-7. PMID 26566913. S2CID 189866517.
  4. Palma JA, Kaufmann H (February 2020). "Management of Orthostatic Hypotension". Continuum. 26 (1): 154–177. doi:10.1212/CON.0000000000000816. PMC 7339914. PMID 31996627.
  5. Kaufmann H, Freeman R, Biaggioni I, Low P, Pedder S, Hewitt LA, et al. (July 2014). "Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial". Neurology. 83 (4): 328–35. doi:10.1212/WNL.0000000000000615. PMC 4115605. PMID 24944260.
  6. Hauser RA, Isaacson S, Lisk JP, Hewitt LA, Rowse G (April 2015). "Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B)". Movement Disorders. 30 (5): 646–54. doi:10.1002/mds.26086. PMID 25487613.
  7. "Highlights of prescribing information for Northeratm (droxidopa)" (PDF). Chelsea Therapeutics, Inc. 2014.
  8. Robertson D (March 2008). "The pathophysiology and diagnosis of orthostatic hypotension". Clinical Autonomic Research. 18 (Supplement 1): 2–7. doi:10.1007/s10286-007-1004-0. PMID 18368300. S2CID 15693501.
  9. "FDA grants accelerated approval to NORTHERA (droxidopa) for patients with symptomatic NOH". news-medical.net. February 18, 2014.
  10. Chen JJ, Han Y, Tang J, Portillo I, Hauser RA, Dashtipour K (December 2018). "Standing and Supine Blood Pressure Outcomes Associated With Droxidopa and Midodrine in Patients With Neurogenic Orthostatic Hypotension: A Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials". The Annals of Pharmacotherapy. 52 (12): 1182–1194. doi:10.1177/1060028018786954. PMID 29972032. S2CID 49674644.
  11. "Lundbeck Announces Availability of NORTHERATM (droxidopa) Capsules in the U.S. for Symptomatic Neurogenic Orthostatic Hypotension" (PDF). Lundbeck NA Ltd. Archived from the original (PDF) on 2018-09-20. Retrieved 2015-11-02.
  12. Buoli M, Serati M, Cahn W (2016). "Alternative pharmacological strategies for adult ADHD treatment: a systematic review". Expert Rev Neurother. 16 (2): 131–44. doi:10.1586/14737175.2016.1135735. PMID 26693882. S2CID 33004517.
  13. Adler LA, Gorny SW (January 2019). "Pilot Study of Droxidopa With Carbidopa in Adults With ADHD". J Atten Disord. 23 (2): 189–198. doi:10.1177/1087054715580393. PMID 25907673. S2CID 20990991.
  • "Droxidopa". Drug Information Portal. U.S. National Library of Medicine.
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