Bedaquiline

Last updated

Bedaquiline
Bedaquiline.svg
Clinical data
Trade names Sirturo
Other namesBedaquiline fumarate, [1] TMC207, [2] R207910, AIDS222089
AHFS/Drugs.com Monograph
MedlinePlus a613022
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding >99.9% [6]
Metabolism Liver, by CYP3A4 [7]
Elimination half-life 5.5 months [7]
Excretion fecal [7]
Identifiers
  • (1R,2S)-1-(6-Bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C32H31BrN2O2
Molar mass 555.516 g·mol−1
3D model (JSmol)
  • 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, sold under the brand name Sirturo, is a medication used for the treatment of active tuberculosis. [1] Specifically, it is used to treat multi-drug-resistant tuberculosis along with other medications for tuberculosis. [1] [8] [9] It is taken by mouth. [3]

Contents

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. [10] 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. [11]

Medical uses

Its use was approved in December 2012 by the US 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. [12]

As of 2013, both the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) recommend (provisionally) that bedaquiline be reserved for people with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed. [13] [14] [ needs update ]

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] Everyone on bedaquiline should have monitoring with a baseline and repeated ECGs. [3] If a person has a QTcF of > 500 ms or a significant ventricular arrythmia, bedaquiline and other QT prolonging drugs should be stopped.[ citation needed ]

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. [16] Ten deaths occurred in the bedaquiline group out of 79, while two occurred in the placebo group, out of 81. [17] 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 person had stopped receiving bedaquiline. [16] However, there is still significant concern for the higher mortality in people 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. [16] [18]

Drug interactions

Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the liver enzyme responsible for oxidative metabolism of the drug. [3] 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. [3]

Mechanism of action

Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. [19] It is the first member of a class of drugs called the diarylquinolines. [19] Bedaquiline is bactericidal. [19] ATP production is required for cellular energy production and its loss leads inhibition of mycobacterial growth within hours of the addition of bedaquiline. [20] The onset of bedaquiline-induced mycobacterial cell death does not occur until several days after treatment, but nonetheless kills consistently thereafter. [20]

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. [21]

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

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. [24] 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. [25]

When it was approved by the FDA in December 2012, it was the first new medicine for TB in more than forty years. [26] [27]

In 2016, the WHO came under criticism for recommending it as an essential medicine. [28]

The WHO TB program director has pointed out that Janssen will donate $30 million worth (30,000 treatment courses) of bedaquiline over a four-year period. [29]

In 2023, a request to extend the patent on bedaquiline until 2027, was rejected by the Indian patent office. [30] The patent was supposed to expire in July 2023, but J&J's "evergreening" practices will not allow the distribution of generics in several countries heavily afflicted by tuberculosis. [31]

In July 2023, the WHO's Stop TB program and Johnson & Johnson came to an agreement allowing for Stop TB Partnership's Global Drug Facility to produce generic bedaquiline for the majority of low and middle income countries. [32]

In July 2024, the Indian Patent Office’s rejected Johnson & Johnson's application for a pediatric version of bedaquiline, paving the way for more affordable generic alternatives, potentially reducing treatment costs by 80% beyond the primary patent’s expiration in July 2023. [33]

Society and culture

Economics

The cost for six months is approximately US$900 in low-income countries, $3,000 in middle-income countries, and $30,000 in high-income countries. [34]

The public sector invested $455–747 million in developing bedaquiline. This is thought to be 1.6x to 5.1x what the owner, Janssen Biotech, invested (estimated at $90–240 million). If capitalized and risk-adjusted, these costs become $647–1,201 million and $292–772 million, respectively. [35]

Research

In vitro experiments have indicated that bedaquiline may also target the mitochondrial ATP synthase of malignant mammalian cells and reduce the rate of metastasis. [36]

Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway. [18] It has been shown to improve cure rates of smear-positive multidrug-resistant tuberculosis, though with some concern for increased rates of death. [17]

Small studies have also examined its use as salvage therapy for non-tuberculous mycobacterial infections. [18]

It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid + moxifloxacin + pyrazinamide). [37] [38]

Related Research Articles

<span class="mw-page-title-main">Tuberculosis</span> Infectious disease

Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is an infectious disease usually caused by Mycobacterium tuberculosis (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in which case it is known as latent tuberculosis. Around 10% of latent infections progress to active disease which, if left untreated, kill about half of those affected. Typical symptoms of active TB are chronic cough with blood-containing mucus, fever, night sweats, and weight loss. Infection of other organs can cause a wide range of symptoms.

Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It has US Food and Drug Administration (FDA) approval to treat rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. Tumor necrosis factor alpha (TNFα) is the "master regulator" of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.

<span class="mw-page-title-main">Rifampicin</span> Antibiotic medication

Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires' disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.

<span class="mw-page-title-main">Amoxicillin/clavulanic acid</span> Combination antibiotic medication

Amoxicillin/clavulanic acid, also known as co-amoxiclav or amox-clav, sold under the brand name Augmentin, among others, is an antibiotic medication used for the treatment of a number of bacterial infections. It is a combination consisting of amoxicillin, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor. It is specifically used for otitis media, streptococcal pharyngitis, pneumonia, cellulitis, urinary tract infections, and animal bites. It is taken by mouth or by injection into a vein.

<span class="mw-page-title-main">Management of tuberculosis</span> Disease treatment

Management of tuberculosis refers to techniques and procedures utilized for treating tuberculosis (TB), or simply a treatment plan for TB.

<span class="mw-page-title-main">4-Aminosalicylic acid</span> Anti-tuberculosis and anti-inflammatory drug

4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the brand name Paser among others, is an antibiotic primarily used to treat tuberculosis. Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.

<span class="mw-page-title-main">Amikacin</span> Antibiotic medication

Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.

<span class="mw-page-title-main">Moxifloxacin</span> Antibiotic

Moxifloxacin is an antibiotic, used to treat bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It can be given by mouth, by injection into a vein, and as an eye drop.

<span class="mw-page-title-main">Rifabutin</span> Chemical compound

Rifabutin (Rfb) is an antibiotic used to treat tuberculosis and prevent and treat Mycobacterium avium complex. It is typically only used in those who cannot tolerate rifampin such as people with HIV/AIDS on antiretrovirals. For active tuberculosis it is used with other antimycobacterial medications. For latent tuberculosis it may be used by itself when the exposure was with drug-resistant TB.

<span class="mw-page-title-main">Rifapentine</span> Chemical compound

Rifapentine, sold under the brand name Priftin, is an antibiotic used in the treatment of tuberculosis. In active tuberculosis it is used together with other antituberculosis medications. In latent tuberculosis it is typically used with isoniazid. It is taken by mouth.

TB Alliance is a not-for-profit product development partnership (PDP) dedicated to the discovery and development of new, faster-acting and affordable tuberculosis (TB) medicines. Since its inception in 2000, TB Alliance has worked to grow the field of available treatments for TB and now manages the largest pipeline of new TB drugs in history. It was founded in Cape Town, South Africa, and has since expanded. It is headquartered in New York City and has a regional office in Pretoria.

<span class="mw-page-title-main">Extensively drug-resistant tuberculosis</span> Tuberculosis that is resistant to the most effective drugs

Extensively drug-resistant tuberculosis (XDR-TB) is a form of tuberculosis caused by bacteria that are resistant to some of the most effective anti-TB drugs. XDR-TB strains have arisen after the mismanagement of individuals with multidrug-resistant TB (MDR-TB).

<span class="mw-page-title-main">Multidrug-resistant tuberculosis</span> Medical condition

Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampicin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).

<span class="mw-page-title-main">Pretomanid</span> Chemical compound

Pretomanid is an antibiotic medication used for the treatment of multi-drug-resistant tuberculosis affecting the lungs. It is generally used together with bedaquiline and linezolid. It is taken by mouth.

Koen Andries is a Belgian Janssen Pharmaceutica scientist and professor at the University of Antwerp. In 2005 he and his team published a discovery about a new di-Aryl-Quinoline-based drug (R207910), now called bedaquiline, which promises a shorter and simpler treatment for drug resistant Tuberculosis (TB).

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Anil Koul is a scientist and former Director of the CSIR-Institute of Microbial Technology (IMTECH), a premier biomedical and biotechnology research institution under Council of Scientific and Industrial Research (CSIR) under Ministry of Science and Technology, Govt. of India.

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References

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  17. 1 2 Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al. (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.
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