Bedaquiline

Last updated

Bedaquiline
Bedaquiline.svg
Clinical data
Trade names Sirturo
Other namesBedaquiline fumarate, [1] TMC207, [2] R207910, AIDS222089
AHFS/Drugs.com Monograph
MedlinePlus a613022
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding >99.9% [3]
Metabolism Liver, by CYP3A4 [4]
Elimination half-life 5.5 months [4]
Excretion fecal [4]
Identifiers
  • (1R,2S)-1-(6-Bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C32H31BrN2O2
Molar mass 555.516 g·mol−1
3D model (JSmol)
  • Brc1ccc2nc(OC)c(cc2c1)[C@@H](c3ccccc3)[C@](O)(c5c4ccccc4ccc5)CCN(C)C
  • InChI=1S/C32H31BrN2O2/c1-35(2)19-18-32(36,28-15-9-13-22-10-7-8-14-26(22)28)30(23-11-5-4-6-12-23)27-21-24-20-25(33)16-17-29(24)34-31(27)37-3/h4-17,20-21,30,36H,18-19H2,1-3H3/t30-,32-/m1/s1
  • Key:QUIJNHUBAXPXFS-XLJNKUFUSA-N

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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Tuberculosis</span> Infectious disease

Tuberculosis (TB), also known as the "white death", or historically as consumption, is an infectious disease usually caused by Mycobacterium tuberculosis (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in which case it is known as latent tuberculosis. Around 10% of latent infections progress to active disease which, if left untreated, kill about half of those affected. Typical symptoms of active TB are chronic cough with blood-containing mucus, fever, night sweats, and weight loss. Infection of other organs can cause a wide range of symptoms.

<span class="mw-page-title-main">Rifampicin</span> Antibiotic medication

Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires' disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.

<span class="mw-page-title-main">Tuberculosis management</span>

Tuberculosis management describes the techniques and procedures utilized for treating tuberculosis (TB).

<span class="mw-page-title-main">Tibotec</span>

Tibotec was a pharmaceutical company with a focus on research and development for the treatment of infectious diseases such as HIV/AIDS and hepatitis C. The company was founded in 1994 and then acquired by Johnson & Johnson and merged into its Janssen Pharmaceuticals division in 2002.

<span class="mw-page-title-main">4-Aminosalicylic acid</span> Anti-tuberculosis and anti-inflammatory drug

4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the brand name Paser among others, is an antibiotic primarily used to treat tuberculosis. Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.

<span class="mw-page-title-main">Amikacin</span> Antibiotic medication

Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.

<span class="mw-page-title-main">Moxifloxacin</span> Antibiotic

Moxifloxacin is an antibiotic, used to treat bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It can be given by mouth, by injection into a vein, and as an eye drop.

<span class="mw-page-title-main">Rifabutin</span> Chemical compound

Rifabutin (Rfb) is an antibiotic used to treat tuberculosis and prevent and treat Mycobacterium avium complex. It is typically only used in those who cannot tolerate rifampin such as people with HIV/AIDS on antiretrovirals. For active tuberculosis it is used with other antimycobacterial medications. For latent tuberculosis it may be used by itself when the exposure was with drug-resistant TB.

<span class="mw-page-title-main">Rifapentine</span> Chemical compound

Rifapentine, sold under the brand name Priftin, is an antibiotic used in the treatment of tuberculosis. In active tuberculosis it is used together with other antituberculosis medications. In latent tuberculosis it is typically used with isoniazid. It is taken by mouth.

TB Alliance is a not-for-profit product development partnership (PDP) dedicated to the discovery and development of new, faster-acting and affordable tuberculosis (TB) medicines. Since its inception in 2000, TB Alliance has worked to grow the field of available treatments for TB and now manages the largest pipeline of new TB drugs in history. It was founded in Cape Town, South Africa, and has since expanded. It is headquartered in New York City and has a regional office in Pretoria.

<span class="mw-page-title-main">Extensively drug-resistant tuberculosis</span> Tuberculosis that is resistant to the most effective drugs

Extensively drug-resistant tuberculosis (XDR-TB) is a form of tuberculosis caused by bacteria that are resistant to some of the most effective anti-TB drugs. XDR-TB strains have arisen after the mismanagement of individuals with multidrug-resistant TB (MDR-TB).

<span class="mw-page-title-main">Multidrug-resistant tuberculosis</span> Medical condition

Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).

<span class="mw-page-title-main">Pretomanid</span> Chemical compound

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

Koen Andries is a Belgian Janssen Pharmaceutica scientist and professor at the University of Antwerp. In 2005 he and his team published a discovery about a new di-Aryl-Quinoline-based drug (R207910), now called bedaquiline, which promises a shorter and simpler treatment for drug resistant Tuberculosis (TB).

Delamanid, sold under the brand name Deltyba, is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

Diaryl quinolines (DARQs) are a chemical class of drugs that treat tuberculosis. They target subunit c of mycobacterial ATP synthase, inhibiting the enzyme so mycobacterium tuberculosis cannot synthesise ATP. This effectively kills the bacteria.

<span class="mw-page-title-main">Ceftazidime/avibactam</span> Combination antibiotic medication

Ceftazidime/avibactam, sold under the brand name Avycaz among others, is a fixed-dose combination medication composed of ceftazidime, a cephalosporin antibiotic, and avibactam, a β-lactamase inhibitor. It is used to treat complicated intra-abdominal infections, urinary tract infections, and pneumonia. It is only recommended when other options are not appropriate. It is given by injection into a vein.

<span class="mw-page-title-main">Lefamulin</span> Chemical compound

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<span class="mw-page-title-main">Anil Koul</span> Indian scientist (born 1972)

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References

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  11. ↑ "Press Announcements - FDA approves first drug to treat multi-drug resistant tuberculosis". www.fda.gov. December 2012. Archived from the original on 19 December 2016.
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  15. 1 2 Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, Leimane V, Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, De Paepe E, van Heeswijk RP, Dannemann B (August 2014). "Multidrug-resistant tuberculosis and culture conversion with bedaquiline". The New England Journal of Medicine. 371 (8): 723–32. doi: 10.1056/NEJMoa1313865 . PMID   25140958.
  16. ↑ "BPaMZ". TB Alliance. 12 July 2016. Archived from the original on 19 February 2017.
  17. ↑ "Two new drug therapies might cure every form of tuberculosis". New Scientist. Archived from the original on 20 February 2017.
  18. ↑ Drugs.com: Sirturo Side Effects Archived 2013-09-23 at the Wayback Machine
  19. 1 2 3 "Prescribing Information for Bedaquiline" (PDF). Archived (PDF) from the original on 24 August 2013. Retrieved 28 April 2014.
  20. 1 2 3 Cox E, Laessig K (August 2014). "FDA approval of bedaquiline--the benefit-risk balance for drug-resistant tuberculosis". The New England Journal of Medicine. 371 (8): 689–91. doi: 10.1056/NEJMp1314385 . PMID   25140952.
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  22. 1 2 Koul A, Vranckx L, Dhar N, Göhlmann HW, Özdemir E, Neefs JM, Schulz M, Lu P, Mørtz E, McKinney JD, Andries K, Bald D (February 2014). "Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism". Nature Communications. 5 (1): 3369. Bibcode:2014NatCo...5.3369K. doi:10.1038/ncomms4369. PMC   3948051 . PMID   24569628.
  23. ↑ Andries K, Villellas C, Coeck N, Thys K, Gevers T, Vranckx L, Lounis N, de Jong BC, Koul A (10 July 2014). "Acquired resistance of Mycobacterium tuberculosis to bedaquiline". PLOS ONE. 9 (7): e102135. Bibcode:2014PLoSO...9j2135A. doi: 10.1371/journal.pone.0102135 . PMC   4092087 . PMID   25010492.
  24. ↑ Fiorillo M, Scatena C, Naccarato AG, Sotgia F, Lisanti MP (May 2021). "Bedaquiline, an FDA-approved drug, inhibits mitochondrial ATP production and metastasis in vivo, by targeting the gamma subunit (ATP5F1C) of the ATP synthase" (PDF). Cell Death and Differentiation. 28 (9): 2797–2817. doi:10.1038/s41418-021-00788-x. PMC   8408289 . PMID   33986463. S2CID   234496165.
  25. ↑ Protopopova M, Bogatcheva E, Nikonenko B, Hundert S, Einck L, Nacy CA (May 2007). "In search of new cures for tuberculosis" (PDF). Medicinal Chemistry. 3 (3): 301–16. doi:10.2174/157340607780620626. PMID   17504204.[ permanent dead link ]
  26. ↑ de Jonge MR, Koymans LH, Guillemont JE, Koul A, Andries K (June 2007). "A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910". Proteins. 67 (4): 971–80. doi: 10.1002/prot.21376 . PMID   17387738. S2CID   41795564.
  27. ↑ Walker J, Tadena N (31 December 2012). "J&J Tuberculosis Drug Gets Fast-Track Clearance". Wall Street Journal. Archived from the original on 23 September 2015. Retrieved 1 January 2013.
  28. ↑ Edney A (31 December 2012). "J&J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB". Bloomberg.com. Bloomberg. Archived from the original on 4 January 2013. Retrieved 1 January 2013.
  29. ↑ "FDA Approves 1st New Tuberculosis Drug in 40 Years". ABC News. Archived from the original on 4 January 2013. Retrieved 31 December 2012.
  30. ↑ Thomas K (31 December 2012). "F.D.A. Approves New Tuberculosis Drug". The New York Times. Archived from the original on 8 January 2013. Retrieved 31 December 2012.
  31. ↑ Pinzler J, Mischke T (2016). "Die WHO - Im Griff der Lobbyisten?". Arte TV. Archived from the original on 24 April 2020. Retrieved 8 April 2020.
  32. ↑ UNOPS (2015). "Stop TB Partnership, Global Drug Facility (GDF), The Bedaquiline Donation Program". www.stoptb.org. Archived from the original on 11 June 2020. Retrieved 8 April 2020.
  33. ↑ Dhillon, Amrit (29 March 2023). "Victory over big pharma opens door to cheaper tuberculosis drugs". The Guardian. ISSN   0261-3077 . Retrieved 11 July 2023.
  34. ↑ "MSF demands J&J give up its patent monopoly on TB drug to put lives over profits". Médecins Sans Frontières Access Campaign. 26 April 2023. Retrieved 11 July 2023.
  35. ↑ "Global Drug Facility Update on Access to Bedaquiline | Stop TB Partnership".
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