Bedaquiline

Bedaquiline
Clinical data
Trade names Sirturo
AHFS/Drugs.com Monograph
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% [1]
Metabolism Liver, by CYP3A4[2]
Biological half-life 5.5 months [2]
Excretion fecal[2]
Identifiers
Synonyms Bedaquiline fumarate,[3] TMC207,[4] R207910, AIDS222089
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C32H31BrN2O2
Molar mass 555.5 g/mol
3D model (JSmol)

Bedaquiline, sold under the brand name Sirturo, is a medication used to treat active tuberculosis.[3] It is specifically used to treat multidrug-resistant tuberculosis (MDR-TB) when other treatment cannot be used. It should be used along with at least three other medications for tuberculosis.[5][3] It is used by mouth.[5]

Common side effects include nausea, joint pains, headaches, and chest pain. Serious side effects include QT prolongation, liver dysfunction, and an increased risk of death.[3] While harm during pregnancy has not been found, it has not been well studied in this population.[6] It is in the diarylquinoline antimycobacterial class of medications. It works by blocking the ability of M. tuberculosis to make adenosine 5'-triphosphate (ATP).[3]

Bedaquiline was approved for medical use in the United States in 2012.[3] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] The cost for six months is approximately $900 USD in low income countries, $3,000 USD in middle income countries, and $30,000 USD in high income countries.[5]

Medical uses

Its use was formally approved (Dec 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.[8]

As of 2013 Both the World Health Organization (WHO) and US Centers for Disease Control (CDC) have recommended (provisionally) that bedaquiline be reserved for patients with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed.[9][10]

Clinical trials

Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway.[11] 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).[12]

Small studies have also examined its use as salvage therapy for non-tuberculous mycobacterial infections.[11]

It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid + moxifloxacin + pyrazinamide).[13][14]

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.[15] All patients on bedaquiline should have monitoring with a baseline and repeated ECGs.[16] If a patient has a QTcF of > 500ms or a significant ventricular arrythmia, bedaquiline and other QT prolonging drugs should be stopped.

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.[17] 10 deaths occurred in the bedaquiline group out of 79, while 2 occurred in the placebo group, out of 81.[12] Of the 10 deaths on bedaquiline, 1 was due to a motor vehicle accident, 5 were judged as due to progression of the underlying tuberculosis and 3 were well after the patient had stopped receiving bedaquiline.[17] However there is still significant concern for the higher mortality in patients treated with bedaquiline, leading to the recommendation to limit its use to situations where a 4 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.[17][11]

Drug interactions

Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the hepatic enzyme responsible for oxidative metabolism of the drug.[16] 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[16]

Since bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided.[9] Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones and clofazimine.

Mode of action

Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. ATP production is required for cellular energy production and its loss leads to cell death, even in dormant or nonreplicating mycobacteria.[18] It is the first member of a new class of drugs called the diarylquinolines.[18] Bedquiline is bactericidal.[18]

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.[19]

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.[20] It was discovered by a team led by Koen Andries at Janssen Pharmaceutica.[21]

Bedaquiline was approved for medical use in the United States in 2012.[3]

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.[22] 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.[23]

When it was approved by the FDA on the 28th December 2012, it was the first new medicine for TB in more than forty years.[24][25]

References

  1. ↑ "Sirturo: Clinical Pharmacology". Retrieved 28 April 2014.
  2. 1 2 3 "Bedaquiline". Archived from the original on 20 May 2013. Retrieved 28 April 2014.
  3. 1 2 3 4 5 6 7 "Bedaquiline Fumarate". The American Society of Health-System Pharmacists. Retrieved 8 December 2016.
  4. ↑ Diacon AH, Pym A, Grobusch M, et al. (2009). "The diarylquinoline TMC207 for multidrug-resistant tuberculosis.". N Engl J Med. 360 (23): 2397–405. PMID 19494215. doi:10.1056/NEJMoa0808427.
  5. 1 2 3 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). (PDF). World Health Organization. 2015. p. vii, 29. ISBN 9789241209946. Retrieved 10 December 2016.
  6. ↑ "Bedaquiline (Sirturo) Use During Pregnancy". www.drugs.com. Retrieved 10 December 2016.
  7. ↑ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016.
  8. ↑ "Press Announcements - FDA approves first drug to treat multi-drug resistant tuberculosis". www.fda.gov. Dec 2012.
  9. 1 2 Centers for Disease Control and Prevention (2013-10-25). "Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis". MMWR. 62 (RR-09): 1–12. ISSN 1545-8601. PMID 24157696.
  10. ↑ WHO (2013). The use of bedaquiline in the treatment of multidrug-resistant tuberculosis : interim policy guidance.
  11. 1 2 3 Field, Stephen K. (2015-07-01). "Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?". Therapeutic Advances in Chronic Disease. 6 (4): 170–184. ISSN 2040-6223. PMC 4480545 Freely accessible. PMID 26137207. doi:10.1177/2040622315582325.
  12. 1 2 Diacon, Andreas H.; Pym, Alexander; Grobusch, Martin P.; de los Rios, Jorge M.; Gotuzzo, Eduardo; Vasilyeva, Irina; Leimane, Vaira; Andries, Koen; Bakare, Nyasha (2014-08-21). "Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline". New England Journal of Medicine. 371 (8): 723–732. ISSN 0028-4793. PMID 25140958. doi:10.1056/NEJMoa1313865.
  13. ↑ BPaMZ @ TB Alliance
  14. ↑ Two new drug therapies might cure every form of tuberculosis. Feb 2017
  15. ↑ Drugs.com: Sirturo Side Effects
  16. 1 2 3 "Prescribing Information for Bedaquiline" (PDF). Retrieved 28 April 2014.
  17. 1 2 3 Cox, Edward; Laessig, Katherine (2014-08-21). "FDA Approval of Bedaquiline — The Benefit–Risk Balance for Drug-Resistant Tuberculosis". New England Journal of Medicine. 371 (8): 689–691. ISSN 0028-4793. PMID 25140952. doi:10.1056/NEJMp1314385.
  18. 1 2 3 Worley, Marylee V.; Estrada, Sandy J. (2014-11-01). "Bedaquiline: A Novel Antitubercular Agent for the Treatment of Multidrug-Resistant Tuberculosis". Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 34 (11): 1187–1197. ISSN 1875-9114. doi:10.1002/phar.1482.
  19. ↑ Andries, Koen; Villellas, Cristina; Coeck, Nele; Thys, Kim; Gevers, Tom; Vranckx, Luc; Lounis, Nacer; Jong, Bouke C. de; Koul, Anil (2014-07-10). "Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline". PLOS ONE. 9 (7): e102135. ISSN 1932-6203. PMC 4092087 Freely accessible. PMID 25010492. doi:10.1371/journal.pone.0102135.
  20. ↑ Protopopova M, Bogatcheva E, Nikonenko B, Hundert S, Einck L, Nacy CA (May 2007). "In search of new cures for tuberculosis" (PDF). Med Chem. 3 (3): 301–16. PMID 17504204. doi:10.2174/157340607780620626.
  21. ↑ 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. PMID 17387738. doi:10.1002/prot.21376.
  22. ↑ Walker, Joseph; Tadena, Nathalie (December 31, 2012). "J&J Tuberculosis Drug Gets Fast-Track Clearance". Wall Street Journal. Retrieved 2013-01-01.
  23. ↑ Edney, Anna (December 31, 2012). "J&J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB". Bloomberg. Retrieved 2013-01-01.
  24. ↑ "FDA Approves 1st New Tuberculosis Drug in 40 Years". ABC News. Retrieved 31 December 2012.
  25. ↑ "F.D.A. Approves New Tuberculosis Drug". New York Times. Retrieved 31 December 2012.
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