Bedaquiline

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Bedaquiline
Bedaquiline.svg
Systematic (IUPAC) name
(1R,2S)-1-(6-Bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol
Clinical data
Trade names Sirturo
License data
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration		 Oral
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Protein binding >99.9% [1]
Metabolism hepatic, by CYP3A4 [2]
Biological half-life 5.5 months [2]
Excretion fecal [2]
Identifiers
CAS Number 843663-66-1
ATC code J04AK05 (WHO)
PubChem CID 5388906
ChemSpider 4534966
UNII 78846I289Y
ChEBI CHEBI:72292 YesY
ChEMBL CHEMBL376488
Synonyms TMC207;[3] R207910; AIDS222089
Chemical data
Formula C32H31BrN2O2
Molar mass 555.5 g/mol

Bedaquiline (trade name Sirturo, code names TMC207 and R207910[3]) is a medication used to treat tuberculosis.

It was discovered by a team led by Koen Andries at Janssen Pharmaceutica.[4] 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,[5][6] and is specifically approved to treat multi-drug-resistant tuberculosis. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[7]

Medical uses[edit]

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.[8]

One of the first published trials of Bedaquiline was a Phase II trial of 47 patients, which showed that the drug was effective in reducing the time to TB-free sputum cultures.[9] A subsequent phase II efficacy trial was published in 2010 and sponsored by Tibotec and the TB Alliance.[10]

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.[11] 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.[12]

It was formally approved for use by the U.S. Food and Drug Administration (FDA) for use in tuberculosis (TB) treatment, as part of a fast-track approval for use only in cases of multi-drug-resistant tuberculosis, and the more resistant extensively drug resistant tuberculosis.

There is considerable controversy over the approval for the drug, as the FDA's ruling was based on a surrogate outcome (sputum cultures) as opposed to patient deaths. In the clinical trials used for approval, the patients taking bedaquiline were more likely to die (a rate of death of 11.4% in the treatment group, compared to 2.5% in the control group[13]), even though they had resolution of TB based on sputum cultures.[14] For that reason, the label comes with a warning with the heading "WARNINGS: INCREASED MORTALITY; QT PROLONGATION" that says "Only use SIRTURO when an effective treatment regimen cannot otherwise be provided [see Indications and Usage (1) and Warnings and Precautions (5.1)]." [15]

Adverse effects[edit]

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 death (as quoted above) and arrhythmias, as it may induce long QT syndrome by blocking the hERG channel.[16]

The following table provides a summary of adverse drug reactions of bedaquiline, as evidenced by one study:[2][17]

Side effect Treatment/% (n=79) Placebo/% (n=81)
Nausea 38.0 32.1
Arthralgia 32.9 22.2
Headache 27.8 12.3
Elevated Transaminases 8.9 1.2
Elevated Blood Amylase 2.5 1.2

Drug interactions[edit]

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.[17] 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[17]

Mode of action[edit]

Bedaquiline affects the proton pump for ATP synthase. This mechanism is unlike that of all other quinolone antibiotics, whose target is DNA gyrase.[18]

See also[edit]

References[edit]

  1. ^ "Sirturo: Clinical Pharmacology". Retrieved 28 April 2014. 
  2. ^ a b c d "Bedaquiline". Retrieved 28 April 2014. 
  3. ^ a b Diacon AH, Pym A, Grobusch M, et al. (2009). "The diarylquinoline TMC207 for multidrug-resistant tuberculosis.". N Engl J Med 360 (23): 2397–405. doi:10.1056/NEJMoa0808427. PMID 19494215. 
  4. ^ 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. 
  5. ^ "FDA Approves 1st New Tuberculosis Drug in 40 Years". ABC News. Retrieved 31 December 2012. 
  6. ^ "F.D.A. Approves New Tuberculosis Drug". New York Times. Retrieved 31 December 2012. 
  7. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  8. ^ 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. doi:10.2174/157340607780620626. PMID 17504204. 
  9. ^ Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, Mc Neeley DF (June 2009). "The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis". N. Engl. J. Med. 360 (23): 2397–2405. doi:10.1056/NEJMoa0808427. PMID 19494215. 
  10. ^ Matteelli A, Carvalho AC, Dooley KE, Kritski A (June 2010). "TMC207: the first compound of a new class of potent anti-tuberculosis drugs". Future Microbiol 5 (6): 849–58. doi:10.2217/fmb.10.50. PMC 2921705. PMID 20521931. 
  11. ^ Walker, Joseph; Tadena, Nathalie (December 31, 2012). "J&J Tuberculosis Drug Gets Fast-Track Clearance". Wall Street Journal. Retrieved 2013-01-01. 
  12. ^ Edney, Anna (December 31, 2012). "J&J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB". Bloomberg. Retrieved 2013-01-01. 
  13. ^ Mahajan, R. (2013). "Bedaquiline: First FDA-approved tuberculosis drug in 40 years". International Journal of Applied and Basic Medical Research 3 (1): 1–2. doi:10.4103/2229-516X.112228. PMC 3678673. PMID 23776831. 
  14. ^ Avorn, J. (2013). "Approval of a Tuberculosis Drug Based on a Paradoxical Surrogate Measure". JAMA 309 (13): 1349–1350. doi:10.1001/jama.2013.623. PMID 23430122. 
  15. ^ "Sirturo label". 
  16. ^ Drugs.com: Sirturo Side Effects
  17. ^ a b c "Prescribing Information for Bedaquiline" (PDF). Retrieved 28 April 2014. 
  18. ^ Kotz J (June 2005). "Targeting tuberculosis". Nature Chemical Biology. doi:10.1038/nchembio002. 
Nucleic acid inhibitor
Rifamycins/
RNA polymerase inhibitor
Antifolates/DSI
ASA
Protein synthesis inhibitor
Aminoglycosides
Oxazolidone
Cell envelope antibiotic
Peptidoglycan layer
Arabinogalactan layer
Mycolic acid layer
Other/unknown
Combinations
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