Chemistry:Bedaquiline

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Short description: Medication used to treat tuberculosis
Bedaquiline
Bedaquiline.svg
Clinical data
Trade namesSirturo
Other namesBedaquiline fumarate,[1] TMC207,[2] R207910, AIDS222089
AHFS/Drugs.comMonograph
MedlinePlusa613022
License data
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding>99.9%[3]
MetabolismLiver, by CYP3A4[4]
Elimination half-life5.5 months[4]
Excretionfecal[4]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC32H31BrN2O2
Molar mass555.516 g·mol−1
3D model (JSmol)

Bedaquiline, sold under the brand name Sirturo, is a medication used to treat active tuberculosis.[1] Specifically, it is used to treat multi-drug-resistant tuberculosis (MDR-TB) along with other medications for tuberculosis.[1][5][6] It is used by mouth.[7]

Common side effects include nausea, joint pains, headaches, and chest pain.[1] Serious side effects include QT prolongation, liver dysfunction, and an increased risk of death.[1] While harm during pregnancy has not been found, it has not been well studied in this population.[8] It is in the diarylquinoline antimycobacterial class of medications.[1] It works by blocking the ability of M. tuberculosis to make adenosine 5'-triphosphate (ATP).[1]

Bedaquiline was approved for medical use in the United States in 2012.[1] It is on the World Health Organization's List of Essential Medicines.[9] The cost for six months is approximately US$900 in low-income countries, US$3,000 in middle-income countries, and US$30,000 in high-income countries.[7]

The public sector invested US$455–747 million in developing bedaquiline. This is thought to be 1.6× to 5.1× what the owner, Janssen Biotech, invested (estimated at US$90–240 million). If capitalized and risk-adjusted, these costs become US$647–1,201 million and US$292–772 million, respectively.[10]

Medical uses

Its use was approved in December 2012 by the U.S. Food and Drug Administration (FDA) for use in tuberculosis (TB) treatment, as part of a Fast-Track accelerated approval, for use only in cases of multidrug-resistant tuberculosis, and the more resistant extensively drug resistant tuberculosis.[11]

(As of 2013) both the World Health Organization (WHO) and US Centers for Disease Control (CDC) have recommended (provisionally) that bedaquiline be reserved for people with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed.[12][13]

Clinical trials

Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway.[14] It has been shown to improve cure rates of smear-positive multidrug-resistant tuberculosis, though with some concern for increased rates of death (further detailed in the Adverse effects section).[15]

Small studies have also examined its use as salvage therapy for non-tuberculous mycobacterial infections.[14]

It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid + moxifloxacin + pyrazinamide).[16][17]

Side effects

The most common side effects of bedaquiline in studies were nausea, joint and chest pain, and headache. The drug also has a black-box warning for increased risk of death and arrhythmias, as it may prolong the QT interval by blocking the hERG channel.[18] Everyone on bedaquiline should have monitoring with a baseline and repeated ECGs.[19] If a person has a QTcF of > 500 ms or a significant ventricular arrythmia, bedaquiline and other QT prolonging drugs should be stopped.[citation needed]

There is considerable controversy over the approval for the drug, as one of the largest studies to date had more deaths in the group receiving bedaquiline that those receiving placebo.[20] Ten deaths occurred in the bedaquiline group out of 79, while two occurred in the placebo group, out of 81.[15] Of the 10 deaths on bedaquiline, one was due to a motor vehicle accident, five were judged as due to progression of the underlying tuberculosis and three were well after the person had stopped receiving bedaquiline.[20] However, there is still significant concern for the higher mortality in people treated with bedaquiline, leading to the recommendation to limit its use to situations where a four drug regimen cannot otherwise be constructed, limit use with other medications that prolong the QT interval, and the placement of a prominent black box warning.[20][14]

Drug interactions

Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the liver enzyme responsible for oxidative metabolism of the drug.[19] Co-administration with rifampin, a strong CYP3A4 inducer, results in a 52% decrease in the AUC of the drug. This reduces the exposure of the body to the drug and decreases the antibacterial effect. Co-administration with ketoconazole, a strong CYP3A4 inhibitor, results in a 22% increase in the AUC, and potentially an increase in the rate of adverse effects experienced.[19]

Since bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided.[12] Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones and clofazimine.[citation needed]

Mechanism of action

Bedaquiline blocks the proton pump for ATP synthase of mycobacteria.[21] It is the first member of a new class of drugs called the diarylquinolines.[21] Bedaquiline is bactericidal.[21] ATP production is required for cellular energy production and its loss leads inhibition of mycobacterial growth within hours of the addition of bedaquiline.[22] The onset of bedaquiline-induced mycobacterial cell death does not occur until several days after treatment, but nonetheless kills consistently thereafter.[22]

Resistance

The specific part of ATP synthase affected by bedaquiline is subunit c which is encoded by the gene atpE. Mutations in atpE can lead to resistance. Mutations in drug efflux pumps have also been linked to resistance.[23]

Ongoing research

In vitro experiments have indicated that bedaquiline may also target the mitochondrial ATP synthase of malignant mammalian cells and reduce the rate of metastasis.[24]

History

Bedaquiline was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting, after the drug had been in development for over seven years.[25] It was discovered by a team led by Koen Andries at Janssen Pharmaceutica.[26]

Bedaquiline was approved for medical use in the United States in 2012.[1]

It is manufactured by Johnson & Johnson (J&J), who sought accelerated approval of the drug, a type of temporary approval for diseases lacking other viable treatment options.[27] By gaining approval for a drug that treats a neglected disease, J&J is now able to request expedited FDA review of a future drug.[28]

When it was approved by the FDA on 28 December 2012, it was the first new medicine for TB in more than forty years.[29][30]

In 2016, the WHO came under criticism for recommending it as an essential medicine.[31]

The WHO TB program director has pointed out that Janssen will donate $30 million worth (30,000 treatment courses) of bedaquiline over a four-year period.[32]

In 2023, a request to extend the patent on bedaquiline until 2027 was rejected by the Indian patent office.[33] The patent was supposed to expire in July 2023, but J&J's "evergreening" practices will not allow the distribution of generics in several countries heavily afflicted by tuberculosis.[34]

On July 13, 2023, the WHO's Stop TB program and Johnson & Johnson came to an agreement allowing for Stop TB Partnership's Global Drug Facility to produce generic bedaquiline for the majority of low and middle income countries.[35]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Bedaquiline Fumarate". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/bedaquiline-fumarate.html. 
  2. ↑ "The diarylquinoline TMC207 for multidrug-resistant tuberculosis". The New England Journal of Medicine 360 (23): 2397–405. June 2009. doi:10.1056/NEJMoa0808427. PMID 19494215. 
  3. ↑ "Sirturo: Clinical Pharmacology". http://www.rxlist.com/sirturo-drug/clinical-pharmacology.htm. 
  4. ↑ 4.0 4.1 4.2 "Bedaquiline". http://www.imnotebook.com/content/bedaquiline. 
  5. ↑ "WHO Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB)". https://www.who.int/tb/publications/2018/rapid_communications_MDR/en/. 
  6. ↑ "Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis" (in en). Lancet 392 (10150): 821–834. September 2018. doi:10.1016/S0140-6736(18)31644-1. PMID 30215381. 
  7. ↑ 7.0 7.1 The selection and use of essential medicines. Twentieth report of the WHO Expert Committee 2015 (including 19th WHO Model List of Essential Medicines and 5th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization. 2015. pp. 26–30. WHO technical report series;994. ISBN 9789241209946. 
  8. ↑ "Bedaquiline (Sirturo) Use During Pregnancy". https://www.drugs.com/pregnancy/bedaquiline.html. 
  9. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  10. ↑ "Public investments in the clinical development of bedaquiline". PLOS ONE 15 (9): e0239118. 18 September 2020. doi:10.1371/journal.pone.0239118. PMID 32946474. Bibcode: 2020PLoSO..1539118G. 
  11. ↑ "Press Announcements - FDA approves first drug to treat multi-drug resistant tuberculosis" (in en). Dec 2012. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm. 
  12. ↑ 12.0 12.1 Centers for Disease Control Prevention (October 2013). "Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis". MMWR. Recommendations and Reports 62 (RR-09): 1–12. PMID 24157696. 
  13. ↑ WHO (2013). The use of bedaquiline in the treatment of multidrug-resistant tuberculosis: interim policy guidance.. World Health Organization. https://www.ncbi.nlm.nih.gov/books/NBK154136/. 
  14. ↑ 14.0 14.1 14.2 "Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?". Therapeutic Advances in Chronic Disease 6 (4): 170–84. July 2015. doi:10.1177/2040622315582325. PMID 26137207. 
  15. ↑ 15.0 15.1 "Multidrug-resistant tuberculosis and culture conversion with bedaquiline". The New England Journal of Medicine 371 (8): 723–32. August 2014. doi:10.1056/NEJMoa1313865. PMID 25140958. 
  16. ↑ "BPaMZ". 12 July 2016. Archived from the original on 19 February 2017. https://web.archive.org/web/20170219100904/https://www.tballiance.org/portfolio/regimen/bpamz. 
  17. ↑ "Two new drug therapies might cure every form of tuberculosis". Archived from the original on 20 February 2017. https://web.archive.org/web/20170220094956/https://www.newscientist.com/article/2121354-two-new-drug-therapies-might-cure-every-form-of-tuberculosis/. 
  18. ↑ Drugs.com: Sirturo Side Effects
  19. ↑ 19.0 19.1 19.2 "Prescribing Information for Bedaquiline". http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. 
  20. ↑ 20.0 20.1 20.2 "FDA approval of bedaquiline--the benefit-risk balance for drug-resistant tuberculosis". The New England Journal of Medicine 371 (8): 689–91. August 2014. doi:10.1056/NEJMp1314385. PMID 25140952. 
  21. ↑ 21.0 21.1 21.2 "Bedaquiline: a novel antitubercular agent for the treatment of multidrug-resistant tuberculosis". Pharmacotherapy 34 (11): 1187–97. November 2014. doi:10.1002/phar.1482. PMID 25203970. 
  22. ↑ 22.0 22.1 "Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism". Nature Communications 5 (1): 3369. February 2014. doi:10.1038/ncomms4369. PMID 24569628. Bibcode: 2014NatCo...5.3369K. 
  23. ↑ "Acquired resistance of Mycobacterium tuberculosis to bedaquiline". PLOS ONE 9 (7): e102135. 2014-07-10. doi:10.1371/journal.pone.0102135. PMID 25010492. Bibcode: 2014PLoSO...9j2135A. 
  24. ↑ "Bedaquiline, an FDA-approved drug, inhibits mitochondrial ATP production and metastasis in vivo, by targeting the gamma subunit (ATP5F1C) of the ATP synthase". Cell Death and Differentiation 28 (9): 2797–2817. May 2021. doi:10.1038/s41418-021-00788-x. PMID 33986463. PMC 8408289. http://usir.salford.ac.uk/id/eprint/60419/1/s41418-021-00788-x.pdf. 
  25. ↑ "In search of new cures for tuberculosis". Medicinal Chemistry 3 (3): 301–16. May 2007. doi:10.2174/157340607780620626. PMID 17504204. http://www.sequella.com/docs/TB_Drugs_Review.pdf. [yes|permanent dead link|dead link}}]
  26. ↑ "A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910". Proteins 67 (4): 971–80. June 2007. doi:10.1002/prot.21376. PMID 17387738. 
  27. ↑ "J&J Tuberculosis Drug Gets Fast-Track Clearance". Wall Street Journal. December 31, 2012. https://www.wsj.com/articles/SB10001424127887323320404578213421059138236. 
  28. ↑ "J&J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB". Bloomberg.com (Bloomberg). December 31, 2012. https://www.bloomberg.com/news/2012-12-31/j-j-sirturo-wins-fda-approval-to-treat-drug-resistant-tb.html. 
  29. ↑ "FDA Approves 1st New Tuberculosis Drug in 40 Years". ABC News. https://abcnews.go.com/Health/wireStory/fda-approves-tuberculosis-40-years-18100650. 
  30. ↑ "F.D.A. Approves New Tuberculosis Drug". The New York Times. 2012-12-31. https://www.nytimes.com/2013/01/01/business/fda-approves-new-tuberculosis-drug.html. 
  31. ↑ "Die WHO - Im Griff der Lobbyisten?". 2016. https://www.arte.tv/de/videos/061650-000-A/die-who-im-griff-der-lobbyisten/. 
  32. ↑ UNOPS (2015). "Stop TB Partnership, Global Drug Facility (GDF), The Bedaquiline Donation Program" (in en). http://www.stoptb.org/gdf/drugsupply/bedaquilineDonation.asp. 
  33. ↑ Dhillon, Amrit (2023-03-29). "Victory over big pharma opens door to cheaper tuberculosis drugs" (in en-GB). The Guardian. ISSN 0261-3077. https://www.theguardian.com/global-development/2023/mar/29/victory-over-big-pharma-opens-door-to-cheaper-tuberculosis-drugs-india. 
  34. ↑ "MSF demands J&J give up its patent monopoly on TB drug to put lives over profits" (in en). 2023-04-26. https://www.msfaccess.org/msf-demands-jj-give-its-patent-monopoly-tb-drug-put-lives-over-profits. 
  35. ↑ "Global Drug Facility Update on Access to Bedaquiline | Stop TB Partnership". https://www.stoptb.org/news/global-drug-facility-update-access-to-bedaquiline. 

External links



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