Bedaquiline

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Bedaquiline
File: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
Licence data US FDA:link
Pregnancy
category
  • US: B (No risk in non-human studies)
Legal status
  • ℞ (Prescription only)
Routes of
administration		 Oral
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
Molecular mass 555.5 g/mol
  • 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 (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

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

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

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

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

References

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  16. ↑ Drugs.com: Sirturo Side Effects
  17. ↑ 17.0 17.1 17.2 Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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