Bedaquiline

Bedaquiline
Systematic (IUPAC) name
(1R,2S)-1-(6-Bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol
Clinical data
Trade names Sirturo
Licence data US FDA:link
  • US: B (No risk in non-human studies)
Oral
Pharmacokinetic data
Protein binding >99.9% [1]
Metabolism hepatic, by CYP3A4 <ref name=IM //>
Half-life 5.5 months [2]
Excretion faeces [2]
Identifiers
843663-66-1
J04AK05
PubChem CID 5388906
ChemSpider 4534966
UNII 78846I289Y
ChEBI CHEBI:72292 Yes
ChEMBL CHEMBL376488
Synonyms TMC207;[3] R207910; AIDS222089
Chemical data
Formula C32H31BrN2O2
555.5 g/mol

Bedaquiline (trade name Sirturo, code names TMC207[3] and R207910) is a diarylquinoline anti-tuberculosis drug, which 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 to fight TB in more than forty years,[5][6] and is specifically approved to treat multi-drug-resistant tuberculosis.

Mode of action

Bedaquiline affects the proton pump for ATP synthase. This mechanism is unlike that of the quinolones, whose target is DNA gyrase.[7]

Clinical trials and approval

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 some 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]

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.[15] 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[15]

Adverse 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 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][15]

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

See also

References

  1. ↑ "Sirturo: Clinical Pharmacology". Retrieved 28 April 2014.
  2. ↑ 2.0 2.1 2.2 "Bedaquiline". Retrieved 28 April 2014.
  3. ↑ 3.0 3.1 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. ↑ Kotz J (June 2005). "Targeting tuberculosis". Nature Chemical Biology. doi:10.1038/nchembio002.
  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. ↑ 15.0 15.1 15.2 "Prescribing Information for Bedaquiline" (PDF). Retrieved 28 April 2014.
  16. ↑ Drugs.com: Sirturo Side Effects