Bedaquiline, sold under the brand name Sirturo, is a medication used to treat active
tuberculosis
Tuberculosis (TB) 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 ...
.
Specifically, it is used to treat
multi-drug-resistant tuberculosis
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 rifampin. Some f ...
(MDR-TB) along with other
medications for tuberculosis
Tuberculosis management describes the techniques and procedures utilized for treating tuberculosis (TB).
The medical standard for active TB is a short course treatment involving a combination of isoniazid, rifampicin (also known as Rifampin), py ...
.
It is used by mouth.
Common side effects include nausea, joint pains, headaches, and chest pain.[ Serious side effects include ]QT prolongation
Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, ...
, liver dysfunction, and an increased risk of death.[ While harm during ]pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
has not been found, it has not been well studied in this population. It is in the diarylquinoline antimycobacterial An antimycobacterial is a type of medication used to treat Mycobacteria infections.
Types include:
* Tuberculosis treatment
Tuberculosis management describes the techniques and procedures utilized for treating tuberculosis (TB).
The medical st ...
class of medications.[ It works by blocking the ability of '' M. tuberculosis'' to make ]adenosine 5'-triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
(ATP).[
Bedaquiline was approved for medical use in the United States in 2012.][ It is on the ]World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. 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.[
The public sector invested US$455–747 million in developing bedaquiline. This is thought to be 1.6× to 5.1× what the owner, ]Janssen Biotech
Janssen Pharmaceuticals is a pharmaceutical company headquartered in Beerse, Belgium, and wholly-owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen.
In 1961, Janssen Pharmaceuticals was purchased by New Jersey-based American ...
, invested (estimated at US$90–240 million). If capitalized and risk-adjusted, these costs become US$647–1,201 million and US$292–772 million, respectively.
Medical uses
Its use was approved in December 2012 by the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) for use in tuberculosis
Tuberculosis (TB) 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 ...
(TB) treatment, as part of a Fast-Track accelerated approval The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate endp ...
, for use only in cases of multidrug-resistant tuberculosis
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 rifampin. Some f ...
, and the more resistant extensively drug resistant tuberculosis.
both the World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
(WHO) and US Centers for Disease Control
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(CDC) have recommended (provisionally) that bedaquiline be reserved for people with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed.
Clinical trials
Bedaquiline has been studied in phase IIb
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway. 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).
Small studies have also examined its use as salvage therapy
Salvage therapy, also known as rescue therapy, is a form of therapy given after an ailment does not respond to standard therapy. The most common diseases that require salvage therapy are HIV and various cancers. The term is not clearly defined; it ...
for non-tuberculous mycobacterial infections.
It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid
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.
The most common side effects include ...
+ moxifloxacin
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.
Common side effects incl ...
+ pyrazinamide
Pyrazinamide is a medication used to treat tuberculosis. For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis. It i ...
).[BPaMZ @ TB Alliance]
[Two new drug therapies might cure every form of tuberculosis. Feb 2017]
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
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
, as it may prolong the QT interval by blocking the hERG
hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to th ...
channel. Everyone on bedaquiline should have monitoring with a baseline and repeated ECGs. If a person 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. Ten deaths occurred in the bedaquiline group out of 79, while two occurred in the placebo group, out of 81. 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. 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
In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because
the U.S. Food and Drug Administration specifies that it ...
.
Drug interactions
Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
, the liver enzyme responsible for oxidative metabolism of the drug. Co-administration with rifampin
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 tog ...
, 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
Since bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided. Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones
A quinolone antibiotic is a member of a large group of broad-spectrum antibiotic, broad-spectrum bacteriocidals that share a bicyclic molecule, bicyclic core structure related to the substance 4-Quinolone, 4-quinolone. They are used in human and ...
and clofazimine
Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to sup ...
.
Mechanism of action
Bedaquiline blocks the proton pump
A proton pump is an integral membrane protein pump that builds up a proton gradient across a biological membrane
A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell f ...
for ATP synthase
ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation ...
of mycobacteria. It is the first member of a new class of drugs called the diarylquinolines. Bedaquiline is bactericidal. ATP production is required for cellular energy production and its loss leads inhibition of mycobacterial growth within hours of the addition of bedaquiline. The onset of bedaquiline-induced mycobacterial cell death does not occur until several days after treatment, but nonetheless kills consistently thereafter.
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.
Ongoing research
In vitro experiments have indicated that Bedaquiline may also target the mitochondrial
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
ATP synthase of malignant
Malignancy () is the tendency of a medical condition to become progressively worse.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
mammalian cells and reduce the rate of metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
.
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. It was discovered by a team led by Koen Andries
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 ...
at Janssen Pharmaceutica
Janssen Pharmaceuticals is a pharmaceutical company headquartered in Beerse, Belgium, and wholly-owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen.
In 1961, Janssen Pharmaceuticals was purchased by New Jersey-based American ...
.
Bedaquiline was approved for medical use in the United States in 2012.[
It is manufactured by ]Johnson & Johnson
Johnson & Johnson (J&J) is an American multinational corporation founded in 1886 that develops medical devices, pharmaceuticals, and consumer packaged goods. Its common stock is a component of the Dow Jones Industrial Average and the company i ...
(J&J), who sought accelerated approval The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate endp ...
of the drug, a type of temporary approval for diseases lacking other viable treatment options. 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.
When it was approved by the FDA on 28 December 2012, it was the first new medicine for TB in more than forty years.
In 2016, the WHO came under criticism for recommending it as an essential medicine.
The WHO TB program director has pointed out that Janssen will donate $30 million worth (30,000 treatment courses) of bedaquiline over a 4-year period.
References
External links
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ATP synthase inhibitors