Clinical data | |
---|---|
Trade names | Sirturo |
Other names | Bedaquiline 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 | |
| |
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) | |
| |
|
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]
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]
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 [update], 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]
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]
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]
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]
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]
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]
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. [33]
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. [34]
In vitro experiments have indicated that bedaquiline may also target the mitochondrial ATP synthase of malignant mammalian cells and reduce the rate of metastasis. [35]
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). [36] [37]
{{
cite journal}}
: CS1 maint: overridden setting (
link)
Clinical data | |
---|---|
Trade names | Sirturo |
Other names | Bedaquiline 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 | |
| |
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) | |
| |
|
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]
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]
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 [update], 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]
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]
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]
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]
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]
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]
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. [33]
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. [34]
In vitro experiments have indicated that bedaquiline may also target the mitochondrial ATP synthase of malignant mammalian cells and reduce the rate of metastasis. [35]
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). [36] [37]
{{
cite journal}}
: CS1 maint: overridden setting (
link)