Pretomanid
Clinical data
Trade namesDovprela
Other namesPA-824
AHFS/Drugs.comMonograph
MedlinePlusa619056
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
  • (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b] [1,3]oxazine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H12F3N3O5
Molar mass359.261 g·mol−1
3D model (JSmol)
  • C1[C@@H](COC2=NC(=CN21)[N+](=O)[O-])OCC3=CC=C(C=C3)OC(F)(F)F
  • InChI=1S/C14H12F3N3O5/c15-14(16,17)25-10-3-1-9(2-4-10)7-23-11-5-19-6-12(20(21)22)18-13(19)24-8-11/h1-4,6,11H,5,7-8H2/t11-/m0/s1 ☒N
  • Key:ZLHZLMOSPGACSZ-NSHDSACASA-N ☒N

Pretomanid is an antibiotic medication used for the treatment of multi-drug-resistant tuberculosis affecting the lungs.[4][5] It is generally used together with bedaquiline and linezolid.[4] It is taken by mouth.[4]

The most common side effects include nerve damage, acne, vomiting, headache, low blood sugar, diarrhea, and liver inflammation.[4] It is in the nitroimidazole class of medications.[6]

Pretomanid was approved for medical use in the United States in August 2019,[4][7] and in the European Union in July 2020.[2] Pretomanid was developed by TB Alliance.[8][4][9] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[10] It is on the World Health Organization's List of Essential Medicines.[11]

Medical uses

Pretomanid is indicated in combination with bedaquiline and linezolid, in adults, for the treatment of pulmonary extensively drug resistant (XDR), or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB).[2][1]

Mechanism of action

Pretomanid is activated in the mycobacterium by deazaflavin-dependent nitroreductase (Ddn), an enzyme which uses dihydro-F420 (reduced form), into nitric oxide and a highly reactive metabolite. This metabolite attacks the synthesis enzyme DprE2, which is important for the synthesis of cell wall arabinogalactan, to which mycolic acid would be attached. This mechanism is shared with delamanid. Clinical isolates resistant to this drug tend to have mutations in the biosynthetic pathway for Coenzyme F420.[12]

History

Pretomanid is the generic, nonproprietary name for the novel anti-bacterial drug compound formerly called PA-824.[13] Pretomanid is referred to as "Pa" in regimen abbreviations, such as BPaL. The "preto" part of the compound's name honors Pretoria, South Africa, the home of a TB Alliance clinical development office where much of the drug's development took place, while the "-manid" stem designates compounds with similar chemical structures. This class of drug is variously referred to as nitroimidazoles or nitroimidazooxazines. Development of this compound was initiated because of the urgent need for new antibacterial drugs effective against resistant strains of tuberculosis. Also, current anti-TB drugs are mainly effective against replicating and metabolically active bacteria, creating a need for drugs effective against persisting or latent bacterial infections as often occur in patients with tuberculosis.[14]

Discovery and pre-clinical development

Pretomanid was first identified in 2000, in a series of 100 nitroimidazopyran derivatives synthesized and tested for antitubercular activity, by PathoGenesis (now a subsidiary of Novartis).[15] Importantly, pretomanid has activity against static M. tuberculosis isolates that survive under anaerobic conditions, with bactericidal activity comparable to that of the existing drug metronidazole. Pretomanid requires metabolic activation by Mycobacterium for antibacterial activity. Pretomanid was not the most potent compound in the series against cultures of M. tuberculosis, but it was the most active in infected mice after oral administration. Oral pretomanid was active against tuberculosis in mice and guinea pigs at safely tolerated dosages for up to 28 days.[14]

Limited FDA approval

The U.S. Food and Drug Administration (FDA) approved pretomanid only in combination with bedaquiline and linezolid for treatment of a limited and specific population of adults with extensively drug resistant, treatment-intolerant or nonresponsive multidrug resistant pulmonary tuberculosis.[4] Pretomanid was approved under the Limited Population Pathway (LPAD pathway) for antibacterial and antifungal drugs.[4] The LPAD Pathway was established by Congress under the 21st Century Cures Act to expedite development and approval of antibacterial and antifungal drugs to treat serious or life-threatening infections in a limited population of patients with unmet need. Pretomanid is only the third tuberculosis drug to receive FDA approval in more than 40 years.[4][9]

The FDA granted Pretomanid priority review and orphan drug designation.[4] The FDA granted The Global Alliance for TB Drug Development (TB Alliance) the approval of Pretomanid and a Tropical Disease Priority Review Voucher.[4]

References

  1. 1 2 "Pretomanid tablet". DailyMed. 15 September 2019. Retrieved 25 September 2020.
  2. 1 2 3 "Pretomanid FGK EPAR". European Medicines Agency (EMA). 24 March 2020. Retrieved 25 September 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. ↑ "Dovprela Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  4. 1 2 3 4 5 6 7 8 9 10 11 "FDA approves new drug for treatment-resistant forms of tuberculosis that affects the lungs". U.S. Food and Drug Administration (FDA) (Press release). 14 August 2019. Retrieved 28 August 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  5. ↑ "Drug Trials Snapshots: Pretomanid". U.S. Food and Drug Administration (FDA). 14 August 2019. Retrieved 17 March 2020.
  6. ↑ "Our Pipeline". TB Alliance. 19 July 2015. Retrieved 18 April 2019.
  7. ↑ "Drug Approval Package: Pretomanid". U.S. Food and Drug Administration (FDA). 12 September 2019. Retrieved 25 September 2020.
  8. ↑ "TB Medicine Pretomanid Enters Regulatory Review Process in the United States". TB Alliance. 8 March 2019. Retrieved 18 April 2019.
  9. 1 2 Abutaleb Y (14 August 2019). "New antibiotic approved for drug-resistant tuberculosis". The Washington Post.
  10. ↑ "New Drug Therapy Approvals 2019". U.S. Food and Drug Administration. 31 December 2019. Retrieved 15 September 2020.
  11. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
  12. ↑ Abrahams KA, Batt SM, Gurcha SS, Veerapen N, Bashiri G, Besra GS (June 2023). "DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid". Nature Communications. 14 (1): 3828. Bibcode:2023NatCo..14.3828A. doi:10.1038/s41467-023-39300-z. PMC 10307805. PMID 37380634.
  13. ↑ "PA-824 has a New Generic Name: Pretomanid". TB Alliance. 20 October 2014. Retrieved 18 April 2019.
  14. 1 2 Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. (June 2005). "Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models". Antimicrobial Agents and Chemotherapy. 49 (6): 2294–2301. doi:10.1128/AAC.49.6.2294-2301.2005. PMC 1140539. PMID 15917524.
  15. ↑ Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et al. (June 2000). "A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis". Nature. 405 (6789): 962–966. Bibcode:2000Natur.405..962S. doi:10.1038/35016103. PMID 10879539. S2CID 4428584.
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