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Bedaquiline

Bedaquiline
Bedaquiline.svg
Clinical data
Trade namesSirturo
SynonymsBedaquiline fumarate,[1] TMC207,[2] R207910, AIDS222089
AHFS/Drugs.comMonograph
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% [4]
MetabolismLiver, by CYP3A4[3]
Elimination half-life5.5 months [3]
Excretionfecal[3]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC32H31BrN2O2
Molar mass555.5 g/mol 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, the most effective and safe medicines needed in a health system.[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]

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.[10]

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.[11][12]

Clinical trials

Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway.[13] 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).[14]

Small studies have also examined its use as salvage therapy for non-tuberculous mycobacterial infections.[13]

It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid + moxifloxacin + pyrazinamide).[15][16]

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.[17] All patients on bedaquiline should have monitoring with a baseline and repeated ECGs.[18] If a patient has a QTcF of > 500 ms 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.[19] Ten deaths occurred in the bedaquiline group out of 79, while two occurred in the placebo group, out of 81.[14] 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 patient had stopped receiving bedaquiline.[19] 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 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.[19][13]

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.[18] 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[18]

Since bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided.[11] 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.[20] It is the first member of a new class of drugs called the diarylquinolines.[20] Bedaquiline is bactericidal.[20] ATP production is required for cellular energy production and its loss leads inhibition of mycobacterial growth within hours of the addition of bedaquiline.[21] The onset of bedaquiline-induced mycobacterial cell death does not occur until several days after treatment, but nonetheless kills consistently thereafter. [21]

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.[22]

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.[23] It was discovered by a team led by Koen Andries at Janssen Pharmaceutica.[24]

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.[25] 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.[26]

When it was approved by the FDA on 28 December 2012, it was the first new medicine for TB in more than forty years.[27][28]

References

  1. ^ a b c d e f g h i "Bedaquiline Fumarate". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  2. ^ Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, et al. (June 2009). "The diarylquinoline TMC207 for multidrug-resistant tuberculosis". The New England Journal of Medicine. 360 (23): 2397–405. doi:10.1056/NEJMoa0808427. PMID 19494215.
  3. ^ a b c "Bedaquiline". Archived from the original on 20 May 2013. Retrieved 28 April 2014.
  4. ^ "Sirturo: Clinical Pharmacology". Archived from the original on 28 February 2015. Retrieved 28 April 2014.
  5. ^ "WHO Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB)". WHO. Retrieved 24 April 2019.
  6. ^ Ahmad N, Ahuja SD, Akkerman OW, Alffenaar JC, Anderson LF, Baghaei P, et al. (Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017) (September 2018). "Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis". Lancet. 392 (10150): 821–834. doi:10.1016/S0140-6736(18)31644-1. PMC 6463280. PMID 30215381.
  7. ^ a b 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. Archived (PDF) from the original on 20 December 2016. Retrieved 10 December 2016.
  8. ^ "Bedaquiline (Sirturo) Use During Pregnancy". www.drugs.com. Archived from the original on 20 December 2016. Retrieved 10 December 2016.
  9. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  10. ^ "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.
  11. ^ a b 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.
  12. ^ WHO (2013). The use of bedaquiline in the treatment of multidrug-resistant tuberculosis: interim policy guidance. World Health Organization. Archived from the original on 10 September 2017.
  13. ^ a b c Field SK (July 2015). "Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?". Therapeutic Advances in Chronic Disease. 6 (4): 170–84. doi:10.1177/2040622315582325. PMC 4480545. PMID 26137207.
  14. ^ a b 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.
  15. ^ BPaMZ @ TB Alliance Archived 2017-02-19 at the Wayback Machine
  16. ^ Two new drug therapies might cure every form of tuberculosis. Feb 2017 Archived 2017-02-20 at the Wayback Machine
  17. ^ Drugs.com: Sirturo Side Effects Archived 2013-09-23 at the Wayback Machine
  18. ^ a b c "Prescribing Information for Bedaquiline" (PDF). Archived (PDF) from the original on 24 August 2013. Retrieved 28 April 2014.
  19. ^ a b c 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.
  20. ^ a b c Worley MV, Estrada SJ (November 2014). "Bedaquiline: a novel antitubercular agent for the treatment of multidrug-resistant tuberculosis". Pharmacotherapy. 34 (11): 1187–97. doi:10.1002/phar.1482. PMC 5028565. PMID 25203970.
  21. ^ a b 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...5E3369K. doi:10.1038/ncomms4369. PMC 3948051. PMID 24569628.
  22. ^ 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.
  23. ^ 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]
  24. ^ 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.
  25. ^ 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.
  26. ^ Edney A (31 December 2012). "J&J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB". Bloomberg. Archived from the original on 4 January 2013. Retrieved 1 January 2013.
  27. ^ "FDA Approves 1st New Tuberculosis Drug in 40 Years". ABC News. Archived from the original on 4 January 2013. Retrieved 31 December 2012.
  28. ^ 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.