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| Trade names | Dovprela |
| Other names | PA-824 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a619056 |
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| Routes of administration | By mouth |
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| Chemical and physical data | |
| Formula | C14H12F3N3O5 |
| Molar mass | 359.261 g·mol−1 |
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Pretomanid is anantibiotic medication used for the treatment ofmulti-drug-resistant tuberculosis affecting thelungs.[4][5] It is generally used together withbedaquiline andlinezolid.[4] It is takenby mouth.[4]
The most common side effects includenerve damage,acne, vomiting, headache,low blood sugar, diarrhea, andliver inflammation.[4] It is in thenitroimidazole 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 byTB Alliance.[8][4][9] The USFood and Drug Administration (FDA) considers it to be afirst-in-class medication.[10] It is on theWorld Health Organization's List of Essential Medicines.[11]
Pretomanid is indicated in combination with bedaquiline and linezolid, in adults, for the treatment of pulmonary extensively drug resistant, or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis.[2][1]
Pretomanid is activated in the mycobacterium bydeazaflavin-dependent nitroreductase (Ddn), an enzyme which uses dihydro-F420 (reduced form), intonitric oxide and a highly reactive metabolite. This metabolite attacks the synthesis enzymeDprE2, which is important for the synthesis of cell wallarabinogalactan, to which mycolic acid would be attached. This mechanism is shared withdelamanid. Clinical isolates resistant to this drug tend to have mutations in the biosynthetic pathway forCoenzyme F420.[12]
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.[13]
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).[14] Importantly, pretomanid has activity against staticM. tuberculosis isolates that survive under anaerobic conditions, with bactericidal activity comparable to that of the existing drugmetronidazole. Pretomanid requires metabolic activation byMycobacterium for antibacterial activity. Pretomanid was not the most potent compound in the series against cultures ofM. 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.[13]
The USFood and Drug Administration (FDA) approved pretomanid only in combination withbedaquiline andlinezolid for treatment of a limited and specific population of adults withextensively drug resistant, treatment-intolerant or nonresponsivemultidrug resistant pulmonary tuberculosis.[4][7] Pretomanid was approved under the limited population pathway (LPAD pathway) for antibacterial and antifungal drugs.[4] Pretomanid is only the third tuberculosis drug to receive approval from the FDA in more than 40 years.[4][9]
The FDA granted pretomanidpriority review andorphan drug designations.[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]
Pretomanid is theinternational nonproprietary name, thegeneric name, and the nonproprietary name.[15][16] Pretomanid is referred to as "Pa" in regimen abbreviations, such as BPaL. The "preto" part of the compound's name honorsPretoria, 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 asnitroimidazoles or nitroimidazooxazines.
This article incorporates text from this source, which is in thepublic domain.
