Nitisinone

Last updated

Nitisinone
Nitisinone.svg
Nitisinone (ball-and-stick).png
Clinical data
Trade names Orfadin, others
Other namesNTBC
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life Approximately 54 h (Range: 39 to 86 hours)
Identifiers
  • 2-[2-nitro-4-(trifluoromethyl)benzoyl]
    cyclohexane-1,3-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.218.521 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H10F3NO5
Molar mass 329.231 g·mol−1
3D model (JSmol)
  • O=C(c1ccc(cc1[N+]([O-])=O)C(F)(F)F)C2C(=O)CCCC2=O
  • InChI=1S/C14H10F3NO5/c15-14(16,17)7-4-5-8(9(6-7)18(22)23)13(21)12-10(19)2-1-3-11(12)20/h4-6,12H,1-3H2 Yes check.svgY
  • Key:OUBCNLGXQFSTLU-UHFFFAOYSA-N Yes check.svgY

Nitisinone, sold under the brand name Orfadin among others, is a medication used for the treatment of hereditary tyrosinemia type 1; [2] [4] or for the reduction of urine homogentisic acid in adults with alkaptonuria. [5] Nitisinone is a hydroxyphenyl-pyruvate dioxygenase inhibitor. [2] [4]

Contents

It is available as a generic medication. [6]

Medical uses

Nitisinone (Nityr, Orfadin) is indicated for the treatment of hereditary tyrosinemia type 1 in combination with dietary restriction of tyrosine and phenylalanine. [2] [4] Nitisinone (Harliku) is also indicated for the reduction of urine homogentisic acid in adults with alkaptonuria. [5] [7] [8]

Nitisinone is used to treat hereditary tyrosinemia type 1 [9] (HT-1) and alkaptonuria [10] (AKU) in patients from all ages, in combination with dietary restriction of tyrosine and phenylalanine.

Since its first use for this indication in 1991, [11] it has replaced liver transplantation as the first-line treatment for this condition. [12]

It has been shown that nitisinone is toxic to kissing bugs, [13] tsetse, [14] ticks [15] [16] and mosquitoes. [17] [18] . The substance may be in the host's bloodstream, or spread on surfaces, as it is absorbed through the mosquito's skin. [19]

Adverse effects

The most common adverse reactions (>1%) for nitisinone are elevated tyrosine levels, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, eye pain, blepharitis, cataracts, granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash and alopecia. Nitisinone has several negative side effects; these include but are not limited to: bloated abdomen, dark urine, abdominal pain, feeling of tiredness or weakness, headache, light-colored stools, loss of appetite, weight loss, vomiting, and yellow-colored eyes or skin. [20]

Mechanism of action

The mechanism of action of nitisinone involves inhibition of 4-Hydroxyphenylpyruvate dioxygenase (HPPD). [21] [22] This is a treatment for patients with Tyrosinemia type 1 as it prevents the formation of 4-Maleylacetoacetic acid and fumarylacetoacetic acid, which have the potential to be converted to succinyl acetone, a toxin that damages the liver and kidneys. [12]

Alkaptonuria is caused when an enzyme called homogentisic dioxygenase (HGD) is faulty, leading to a buildup of homogentisate (HGA). Alkaptonuria patients treated with nitisinone produce far less HGA than those not treated (95% less in the urine), because nitisinone inhibits HPPD, resulting in less homogenisate accumulation. Clinical trials are ongoing to test whether nitisinone can prevent ochronosis experienced by older alkaptonuria patients [23]

History

Nitisinone was discovered as part of a program to develop a class of herbicides called HPPD inhibitors. It is a member of the benzoylcyclohexane-1,3-dione family of herbicides, which are chemically derived from a natural phytotoxin, leptospermone, obtained from the Australian bottlebrush plant ( Callistemon citrinus ). [24] HPPD is essential in plants and animals for catabolism, or breaking apart, of tyrosine. [25] In plants, preventing this process leads to destruction of chlorophyll and the death of the plant. [25] In toxicology studies of the herbicide, it was discovered that it had activity against HPPD in rats [26] and humans. [27]

In type I tyrosinemia, a different enzyme involved in the breakdown of tyrosine, fumarylacetoacetate hydrolase is either absent or mutated and doesn't work, leading to very harmful products building up in the body. [28] Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists [11] working on making herbicides in the class of HPPD inhibitors, hypothesized that inhibiting HPPD and controlling tyrosine in the diet could treat this disease. A series of small clinical trials attempted with one of their compounds, nitisinone, were conducted and were successful, leading to nitisinone being brought to market as an orphan drug by Swedish Orphan International, [21] which was later acquired in 2016 by Swedish Orphan Biovitrum (Sobi). [29]

References

  1. ↑ "Health Canada New Drug Authorizations: 2016 Highlights". Health Canada . 14 March 2017. Retrieved 7 April 2024.
  2. 1 2 3 4 "Orfadin- nitisinone capsule". DailyMed. 30 November 2021. Retrieved 5 July 2025.
  3. ↑ "Orfadin- nitisinone suspension". DailyMed. 20 June 2022. Retrieved 5 July 2025.
  4. 1 2 3 4 "Nityr- nitisinone tablet". DailyMed. 24 May 2024. Retrieved 5 July 2025.
  5. 1 2 3 "Highlights of prescribing information - HARLIKU (nitisinone) tablets, for oral use" (PDF). Archived from the original (PDF) on 23 June 2025.
  6. ↑ "2023 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 29 June 2023. Archived from the original on 29 June 2023. Retrieved 29 June 2023.
  7. ↑ "Harliku (nitisinone) FDA Approval History". Drugs.com. 30 June 2025. Retrieved 5 July 2025.
  8. ↑ "FDA Approves Harliku (nitisinone) for the Treatment of Patients with Alkaptonuria". Drugs.com (Press release). 19 June 2025. Retrieved 5 July 2025.
  9. ↑ Das AM (2017). "Clinical utility of nitisinone for the treatment of hereditary tyrosinemia type-1 (HT-1)". The Application of Clinical Genetics. 10: 43–48. doi: 10.2147/TACG.S113310 . ISSN   1178-704X. PMC   5533484 . PMID   28769581.
  10. ↑ Ranganath LR, Psarelli EE, Arnoux JB, Braconi D, Briggs M, Bröijersén A, et al. (1 September 2020). "Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial". The Lancet. Diabetes & Endocrinology. 8 (9): 762–772. doi:10.1016/S2213-8587(20)30228-X. hdl: 11365/1115671 . PMID   32822600.
  11. 1 2 Lock EA (2017). "From Weed Killer to Wonder Drug". In Tanguay RM (ed.). Hereditary Tyrosinemia: Pathogenesis, Screening and Management. Advances in Experimental Medicine and Biology. Vol. 959. Cham: Springer International Publishing. pp. 175–185. doi:10.1007/978-3-319-55780-9_16. ISBN   978-3-319-55780-9. PMID   28755195 . Retrieved 21 May 2025.
  12. 1 2 McKiernan PJ (2006). "Nitisinone in the treatment of hereditary tyrosinaemia type 1". Drugs. 66 (6): 743–750. doi:10.2165/00003495-200666060-00002. PMID   16706549. S2CID   24239547.
  13. ↑ Perdomo HD, Guizzo MG, Barletta AB, Nunes RD, Dias FA, Sorgine MH, et al. (22 August 2016). "Tyrosine Detoxification Is an Essential Trait in the Life History of Blood-Feeding Arthropods". Current Biology. 26 (16): 2188–2193. Bibcode:2016CBio...26.2188S. doi:10.1016/j.cub.2016.06.025. PMID   27476595.
  14. ↑ Haines LR, Casas-Sánchez A, Adung'a VO, Vionette-Amaral RJ, Quek S, Rose C, et al. (26 January 2021). "Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis". PLOS Biology. 19 (1): e3000796. doi: 10.1371/journal.pbio.3000796 . PMC   7837477 . PMID   33497373.
  15. ↑ Matias J, Tang X, Cibichakravarthy B, DePonte K, Wu MJ, Fikrig E, et al. (1 January 2024). "Metabolomic changes associated with acquired resistance to Ixodes scapularis". Ticks and Tick-borne Diseases. 15 (1) 102279. doi: 10.1016/j.ttbdis.2023.102279 . PMID   37972499.
  16. ↑ Duke SO, Burgess ER, Swale DR, McComic SE (1 August 2023). "Defining the toxicological profile of 4-hydroxyphenylpyruvate dioxygenase-directed herbicides to Aedes aegypti and Amblyomma americanum". Pesticide Biochemistry and Physiology. 194 105532. Bibcode:2023PBioP.19405532M. doi: 10.1016/j.pestbp.2023.105532 . PMID   37532340.
  17. ↑ Haines LR, Trett A, Rose C, García N, Sterkel M, McGuinness D, et al. (March 2025). "Anopheles mosquito survival and pharmacokinetic modeling show the mosquitocidal activity of nitisinone". Science Translational Medicine. 17 (791) eadr4827. doi:10.1126/scitranslmed.adr4827. PMID   40138457.
  18. ↑ Sterkel M, Martins AJ, BP Lima J, L Oliveira P, Vergaray Ramirez MA (2022). "On the use of inhibitors of 4-hydroxyphenylpyruvate dioxygenase as a vector-selective insecticide in the control of mosquitoes". Pest Management Science. 78 (2): 692–702. doi:10.1002/ps.6679. PMID   34647418.
  19. ↑ Stavrou-Dowd ZT, Parsons G, Rose C, Brown F, Lees RS, Acosta-Serrano Á, et al. (July 2025). "The β-triketone, nitisinone, kills insecticide-resistant mosquitoes through cuticular uptake". Parasites & Vectors. 18 (1): 316. doi: 10.1186/s13071-025-06939-0 . PMC   12315382 . PMID   40745331.
  20. ↑ Rodenburg IL, Harding CO, Hollak CE, Heiner-Fokkema MR, van Spronsen FJ, van Ginkel WG (December 2019). "Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1". Paediatric Drugs. 21 (6): 413–426. doi:10.1007/s40272-019-00364-4. ISSN   1179-2019. PMC   6885500 . PMID   31667718.
  21. 1 2 Lock EA, Ellis MK, Gaskin P, Robinson M, Auton TR, Provan WM, et al. (August 1998). "From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug". Journal of Inherited Metabolic Disease. 21 (5): 498–506. doi:10.1023/A:1005458703363. PMID   9728330. S2CID   6717818.
  22. ↑ Kavana M, Moran GR (September 2003). "Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione". Biochemistry. 42 (34): 10238–10245. doi:10.1021/bi034658b. PMID   12939152.
  23. ↑ "Alkaptonuria and ochronosis". DermNet. 26 October 2023. Retrieved 22 May 2025.
  24. ↑ Mitchell G, Bartlett DW, Fraser TE, Hawkes TR, Holt DC, Townson JK, et al. (February 2001). "Mesotrione: a new selective herbicide for use in maize". Pest Management Science. 57 (2): 120–128. doi:10.1002/1526-4998(200102)57:2<120::AID-PS254>3.0.CO;2-E. PMID   11455642.
  25. 1 2 Moran GR (January 2005). "4-Hydroxyphenylpyruvate dioxygenase". Archives of Biochemistry and Biophysics. 433 (1): 117–128. doi:10.1016/j.abb.2004.08.015. PMID   15581571.
  26. ↑ Ellis MK, Whitfield AC, Gowans LA, Auton TR, Provan WM, Lock EA, et al. (July 1995). "Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione". Toxicology and Applied Pharmacology. 133 (1): 12–19. Bibcode:1995ToxAP.133...12E. doi:10.1006/taap.1995.1121. PMID   7597701.
  27. ↑ Lindstedt S, Odelhög B (1987). "4-Hydroxyphenylpyruvate dioxygenase from human liver". In Kaufman S (ed.). Metabolism of Aromatic Amino Acids and Amines. Methods in Enzymology. Vol. 142. pp. 139–142. doi:10.1016/S0076-6879(87)42021-1. ISBN   978-0-12-182042-8. PMID   3037254.
  28. ↑ Tanguay RM. "Physician's Guide to Tyrosinemia Type 1" (PDF). National Organization for Rare Disorders. Archived from the original (PDF) on 11 February 2014.
  29. ↑ "Sobi's Orfadin® oral suspension granted European patent | Sobi". www.sobi.com. 19 January 2016. Retrieved 6 July 2025.
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