Pretomanid
{{Short description|Chemical compound}}
{{Use dmy dates|date=March 2020}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| image = Pretomanid.svg
| image_class = skin-invert-image
| alt =
| caption =
| pronounce =
| tradename = Dovprela
| Drugs.com = {{drugs.com|monograph|pretomanid}}
| MedlinePlus = a619056
| DailyMedID = Pretomanid
| pregnancy_AU =
| pregnancy_AU_comment =
| pregnancy_category=
| routes_of_administration = By mouth
| class =
| ATC_prefix = J04
| ATC_suffix = AK08
| legal_AU =
| legal_AU_comment =
| legal_CA =
| legal_CA_comment =
| legal_DE =
| legal_NZ =
| legal_UK =
| legal_US = Rx-only
| legal_EU = Rx-only
| legal_EU_comment = {{cite web | title=Dovprela Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1437.htm | access-date=3 March 2023}}
| legal_UN =
| legal_status =
| bioavailability =
| protein_bound =
| metabolism =
| metabolites =
| onset =
| elimination_half-life =
| duration_of_action =
| excretion =
| CAS_number = 187235-37-6
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 2XOI31YC4N
| PubChem = 456199
| DrugBank = DB05154
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 401693
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D10722
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 227875
| synonyms = PA-824
| IUPAC_name = (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b] [1,3]oxazine
| C=14|H=12|F=3|N=3|O=5
| smiles= C1[C@@H](COC2=NC(=CN21)[N+](=O)[O-])OCC3=CC=C(C=C3)OC(F)(F)F
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = ZLHZLMOSPGACSZ-NSHDSACASA-N
}}
Pretomanid is an antibiotic medication used for the treatment of multi-drug-resistant tuberculosis affecting the lungs.{{cite press release |title=FDA approves new drug for treatment-resistant forms of tuberculosis that affects the lungs |url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-resistant-forms-tuberculosis-affects-lungs |archive-url=https://web.archive.org/web/20190816134154/https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-resistant-forms-tuberculosis-affects-lungs |url-status=dead |archive-date=16 August 2019 |website=U.S. Food and Drug Administration (FDA) |access-date=28 August 2019 |date=14 August 2019}} {{PD-notice}}{{cite web | title=Drug Trials Snapshots: Pretomanid | website=U.S. Food and Drug Administration (FDA) | date=14 August 2019 | url=http://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-pretomanid | archive-url=https://web.archive.org/web/20200930101252/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-pretomanid | url-status=dead | archive-date=30 September 2020 | access-date=17 March 2020}} It is generally used together with bedaquiline and linezolid. It is taken by mouth.
The most common side effects include nerve damage, acne, vomiting, headache, low blood sugar, diarrhea, and liver inflammation. It is in the nitroimidazole class of medications.{{cite web|url=https://www.tballiance.org/portfolio/compound/pretomanid|title=Our Pipeline|website=TB Alliance|date=19 July 2015|access-date=18 April 2019|archive-date=7 April 2019|archive-url=https://web.archive.org/web/20190407043804/https://www.tballiance.org/portfolio/compound/pretomanid|url-status=dead}}
Pretomanid was approved for medical use in the United States in August 2019,{{cite web | title=Drug Approval Package: Pretomanid | website=U.S. Food and Drug Administration (FDA) | date=12 September 2019 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20200917012231/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000TOC.cfm | url-status=dead | archive-date=17 September 2020 | access-date=25 September 2020}} and in the European Union in July 2020.{{cite web | title=Dovprela (previously Pretomanid FGK) EPAR | website=European Medicines Agency (EMA) | date=24 March 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/dovprela-previously-pretomanid-fgk | access-date=25 September 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Pretomanid was developed by TB Alliance.{{cite web|url=https://www.tballiance.org/news/pretomanid-enters-FDA-review|title=TB Medicine Pretomanid Enters Regulatory Review Process in the United States|website=TB Alliance|date=8 March 2019 |access-date=18 April 2019}}{{cite news | last = Abutaleb | first = Yasmeen | url = https://www.washingtonpost.com/health/new-antibiotic-approved-for-drug-resistant-tuberculosis/2019/08/14/559d069a-bde6-11e9-9b73-fd3c65ef8f9c_story.html | title = New antibiotic approved for drug-resistant tuberculosis | newspaper = The Washington Post | date = 14 August 2019 }} The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.{{cite web | title=New Drug Therapy Approvals 2019 | website=U.S. Food and Drug Administration | date=31 December 2019 | url=https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019 | archive-url=https://web.archive.org/web/20200502164101/https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019 | url-status=dead | archive-date=2 May 2020 | access-date=15 September 2020}} It is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}
Medical uses
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.{{cite web | title=Pretomanid tablet | website=DailyMed | date=15 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f1906fc9-cb3c-4e13-8a4a-da76100c1bf3 | access-date=25 September 2020}}
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.{{cite journal | vauthors = Abrahams KA, Batt SM, Gurcha SS, Veerapen N, Bashiri G, Besra GS | title = DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid | journal = Nature Communications | volume = 14 | issue = 1 | pages = 3828 | date = June 2023 | pmid = 37380634 | doi = 10.1038/s41467-023-39300-z | pmc = 10307805 | bibcode = 2023NatCo..14.3828A | doi-access = free }}
History
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.{{cite journal | vauthors = Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, Reynolds RC, Orme IM | title = Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models | journal = Antimicrobial Agents and Chemotherapy | volume = 49 | issue = 6 | pages = 2294–2301 | date = June 2005 | pmid = 15917524 | pmc = 1140539 | doi = 10.1128/AAC.49.6.2294-2301.2005 }}
=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).{{cite journal | vauthors = 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 | title = A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis | journal = Nature | volume = 405 | issue = 6789 | pages = 962–966 | date = June 2000 | pmid = 10879539 | doi = 10.1038/35016103 | s2cid = 4428584 | bibcode = 2000Natur.405..962S }} 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.
Society and culture
= Legal status =
The US 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. Pretomanid was approved under the limited population pathway (LPAD pathway) for antibacterial and antifungal drugs. Pretomanid is only the third tuberculosis drug to receive approval from the FDA in more than 40 years.
The FDA granted pretomanid priority review and orphan drug designations. The FDA granted The Global Alliance for TB Drug Development (TB Alliance) the approval of pretomanid and a tropical disease priority review voucher.
= Names =
Pretomanid is the international nonproprietary name, the generic name, and the nonproprietary name.{{cite journal | vauthors = ((World Health Organization)) | year = 2014 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 72 | journal = WHO Drug Information | volume = 28 | issue = 3 | hdl = 10665/331112 | hdl-access = free | author-link = World Health Organization }}{{cite web |url=https://www.tballiance.org/news/pa-824-has-new-generic-name-pretomanid |title=PA-824 has a New Generic Name: Pretomanid |website=TB Alliance |date=20 October 2014 |access-date=18 April 2019 |archive-date=18 April 2019 |archive-url=https://web.archive.org/web/20190418184408/https://www.tballiance.org/news/pa-824-has-new-generic-name-pretomanid |url-status=dead }} 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.
References
{{reflist}}
{{Antimycobacterials}}
{{Portal bar | Medicine}}
{{Authority control}}
Category:Anti-tuberculosis drugs