Pretomanid

Pretomanid
Names
Trade namesDovprela
Other namesPretomanid FGK, PA-824
IUPAC name
  • (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
Clinical data
Drug classNitroimidazole[1]
Main usesMulti-drug-resistant tuberculosis[2]
Side effectsNerve damage, acne, vomiting, headache, low blood sugar, diarrhea, liver inflammation[3]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
Typical dose200 mg OD[2]
External links
AHFS/Drugs.comMonograph
MedlinePlusa619056
Legal
License data
Legal status
Chemical and physical data
FormulaC14H12F3N3O5
Molar mass359.261 g·mol−1
3D model (JSmol)
SMILES
  • [O-][N+](=O)c1cn2C[C@@H](COc2n1)OCc3ccc(OC(F)(F)F)cc3
InChI
  • 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, sold under the brand name Dovprela, is an antibiotic used to treat multi-drug-resistant tuberculosis affecting the lungs.[3] It is generally used together with bedaquiline and linezolid.[2] It is taken by mouth.[2]

Common side effects include nerve damage, acne, vomiting, headache, low blood sugar, diarrhea, and liver inflammation.[3] Other side effects may include bone marrow suppression, optic neuropathy, and QT prolongation.[5] Safety in pregnancy is unclear.[6] It is in the nitroimidazole class of medications.[1]

Pretomanid was approved for medical use in the United States in 2019 and Europe in 2020.[3][2] It is on the World Health Organization's List of Essential Medicines.[7] In the developing world it cost 364 USD for 6 months in 2019.[8] In the United States this amount costs about 3,800 USD as of 2021.[9] It was developed by the TB Alliance.[1][3]

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][4]

Dosage

It is generally take at a dose of 200 mg per day for at least 6 months.[2]

History

Pretomanid is the generic, nonproprietary name for the novel anti-bacterial drug compound formerly called PA-824.[10] Pretomanid is referred to as "Pa" in regimen abbreviations, such as BPaL. The "preto" prefix 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. The "manid" suffix is used to group compounds with similar chemical structures. This class of drug is variously referred to as nitroimidazoles, nitroimidazooxazines or nitroimidazopyrans. 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.[11]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[12]

Discovery

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).[13] 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.[11]

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.[3] Pretomanid was approved under the Limited Population Pathway (LPAD pathway) for antibacterial and antifungal drugs.[3] 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.[3][14]

The FDA granted Pretomanid priority review and orphan drug designation.[3] The FDA granted The Global Alliance for TB Drug Development (TB Alliance) the approval of Pretomanid and a Tropical Disease Priority Review Voucher.[3]

References

  1. 1 2 3 "Our Pipeline". TB Alliance. Archived from the original on 7 April 2019. Retrieved 18 April 2019.
  2. 1 2 3 4 5 6 7 8 "Pretomanid FGK EPAR". European Medicines Agency (EMA). 24 March 2020. Archived from the original on 20 October 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. 1 2 3 4 5 6 7 8 9 10 "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. Archived from the original on 19 August 2019. Retrieved 28 August 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  4. 1 2 "Pretomanid tablet". DailyMed. 15 September 2019. Archived from the original on 21 October 2021. Retrieved 25 September 2020.
  5. ↑ "Pretomanid Monograph for Professionals". Drugs.com. Retrieved 29 October 2021.
  6. ↑ "Pretomanid Use During Pregnancy". Drugs.com. Retrieved 29 October 2021.
  7. ↑ 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.
  8. ↑ "Price announced for new lifesaving TB drug pretomanid still too high". Médecins Sans Frontières Access Campaign. Archived from the original on 3 March 2021. Retrieved 29 October 2021.
  9. ↑ "Pretomanid Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 19 January 2021. Retrieved 29 October 2021.
  10. ↑ "PA-824 has a New Generic Name: Pretomanid". TB Alliance. Archived from the original on 18 April 2019. Retrieved 18 April 2019.
  11. 1 2 Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, Reynolds RC, Orme IM (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): 2294–301. doi:10.1128/AAC.49.6.2294-2301.2005. PMC 1140539. PMID 15917524.
  12. ↑ "New Drug Therapy Approvals 2019". U.S. Food and Drug Administration. 31 December 2019. Archived from the original on 16 September 2020. Retrieved 15 September 2020.
  13. ↑ Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, Anderson SW, Towell JA, Yuan Y, McMurray DN, Kreiswirth BN, Barry CE, Baker WR (2000). "A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis". Nature. 405 (6789): 962–6. Bibcode:2000Natur.405..962S. doi:10.1038/35016103. PMID 10879539. S2CID 4428584.
  14. ↑ Abutaleb Y (14 August 2019). "New antibiotic approved for drug-resistant tuberculosis". The Washington Post. Archived from the original on 3 December 2020. Retrieved 1 July 2021.
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