Mtb F1FO-ATP synthase
TDR M. tuberculosis strains are inhibited in growth by bedaquiline, with MIC values ranging from 0.125 to 0.5 mg/L[2].
With MIC50 and MIC90 values of 0.03 and 16 mg/L, respectively, bedaquiline has the strongest activity against Mycobacterium avium among slowly growing mycobacteria (SGM). With MIC50 and MIC90 values of 0.13 and >16 mg/L, respectively, for both species, Mycobacterium abscessus subsp. abscessus (M. abscessus) and Mycobacterium abscessus subsp. massiliense (M. massiliense) appear to be more susceptible to bedaquiline than Mycobacterium fortuitum among rapidly growing mycobacteria (RGM). Moderate in vitro activity of bedaquiline against NTM species is also demonstrated[3].
In vitro activity of bedaquiline against Mycobacterium tuberculosis, including multidrug-resistant M tuberculosis, is very good[4].

TDR M. tuberculosis strains are inhibited in growth by bedaquiline, with MIC values ranging from 0.125 to 0.5 mg/L[2].
With MIC50 and MIC90 values of 0.03 and 16 mg/L, respectively, bedaquiline has the strongest activity against Mycobacterium avium among slowly growing mycobacteria (SGM). With MIC50 and MIC90 values of 0.13 and >16 mg/L, respectively, for both species, Mycobacterium abscessus subsp. abscessus (M. abscessus) and Mycobacterium abscessus subsp. massiliense (M. massiliense) appear to be more susceptible to bedaquiline than Mycobacterium fortuitum among rapidly growing mycobacteria (RGM). Moderate in vitro activity of bedaquiline against NTM species is also demonstrated[3].
In vitro activity of bedaquiline against Mycobacterium tuberculosis, including multidrug-resistant M tuberculosis, is very good[4].

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Bedaquiline (TMC207, R207910) displays protonophore activity, shuttling protons across lipid bilayers to collapse the transmembrane pH gradient, as demonstrated using inverted vesicles from Mycobacterium smegmatis and the pH-sensitive fluorophore ACMA.
In inverted vesicles energized with succinate, Bedaquiline (TMC207, R207910) caused a dose-dependent reduction in ACMA fluorescence quenching, with 15 µM completely eliminating the pH gradient.
In inverted vesicles energized with NADH, the uncoupling effect of 15 µM Bedaquiline (TMC207, R207910) was drastically reduced, indicating the effect is influenced by the electron donor used for respiration.
In whole-cell Mycobacterium bovis BCG, Bedaquiline (TMC207, R207910) (1 µM) caused a rapid intracellular pH increase of 0.35 units within 20 minutes in the absence of a transmembrane pH gradient, as measured with the pH-sensitive fluorophore CMFDA, indicating its ability to readily cross membranes and act as a weak base.
Time-kill analysis against Mycobacterium tuberculosis H37Rv showed that Bedaquiline (TMC207, R207910) exerted bactericidal activity over 21 days at 3-, 30-, and 300-fold its MIC90.[2]

BDQ was highly efficacious in a zebrafish model of M. abscessus infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from M. abscessus-induced killing. This was corroborated with reduced numbers of abscesses and cords, considered to be major pathophysiological signs in infected zebrafish. [7]

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In a zebrafish embryo model of M. abscessus infection, treatment with Bedaquiline significantly increased survival rates. At 1 µg/ml for 3 days, survival was significantly improved compared to untreated controls. Treatment with 3 µg/ml for 3 days protected approximately 80% of infected embryos at 13 days post-infection (dpi). Even short treatments of 24 or 48 hours with 3 µg/ml conferred high levels of protection.[7]
Treatment with Bedaquiline (3 µg/ml) also led to a significant decrease in the frequency of pathophysiological signs characteristic of M. abscessus infection in zebrafish, specifically abscesses and extracellular cords, as visualized by fluorescence microscopy.[7]

Intracellular ATP quantification.
Intracellular ATP levels were determined using a 96-well flat-bottom plate, as described previously for M. tuberculosis. M. abscessus was exposed to BDQ or amikacin (negative control) and incubated for 180 min at 32°C. Twenty-five microliters of M. abscessus culture was mixed with an equal volume of the BacTiter-Glo reagent in 96-well flat-bottom white plates and incubated for 5 min in the darkness. Luminescence was detected using a BioTek Cytation 3 multimode reader, and the values obtained were plotted using GraphPad Prism 6 software.[7]

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The protonophore (uncoupler) activity of Bedaquiline (TMC207, R207910) was assessed using inverted membrane vesicles prepared from Mycobacterium smegmatis. Vesicles were energized by adding an electron donor (succinate or NADH) to establish a transmembrane pH gradient. The gradient was monitored by the quenching of fluorescence from the pH-sensitive dye ACMA. Test compounds were added, and their ability to collapse the pH gradient (de-quench fluorescence) was measured and compared to a known protonophore control (SF6847).[2]

Drug susceptibility testing. [7]
The CLSI guidelines were followed to determine the MICs based on the broth microdilution method in CaMHB using an inoculum containing 5 × 106 CFU/ml in the exponential-growth phase. Bacteria (100 μl) were seeded in 96-well plates, and 2 μl of drug at its highest concentration was added to the first wells containing double the volume of bacterial suspension (200 μl). Twofold serial dilutions were then carried out, and incubation with drugs was performed at 30°C for 3 to 5 days. MICs were recorded by visual inspection and by absorbance at 560 nm to confirm visual recording. Experiments were done in triplicate on three independent occasions. Time-kill assay.[7]
Microtiter plates were set up as for MIC determination. Serial dilutions of the bacterial suspension were plated after 0, 24, 48, 72, and 96 h of exposure to different drug concentrations. CFU were enumerated after 4 days of incubation at 30°C.

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The effect of Bedaquiline (TMC207, R207910) on intracellular pH was measured in whole-cell Mycobacterium bovis BCG. Cells were loaded with the pH-sensitive fluorophore CMFDA. Compounds were added to the cell suspension in the absence of a pre-existing pH gradient between the cell interior and exterior. Changes in intracellular pH over time were monitored by measuring fluorescence.
The bactericidal activity of Bedaquiline (TMC207, R207910) was determined by time-kill analysis against Mycobacterium tuberculosis H37Rv. Cultures were treated with multiples of the MIC90 over 21 days. Bacterial viability at various time points was assessed by plating serial dilutions and enumerating colony-forming units (CFU).[2]

Assessment of BDQ efficacy in infected zebrafish. [7]
Rough M. abscessus CIP104536T (ATCC 19977T) carrying pTEC27 (plasmid 30182; Addgene) and expressing the red fluorescent protein tdTomato was prepared and microinjected in zebrafish embryos, according to procedures described earlier. Briefly, mid-log-phase cultures of M. abscessus expressing tdTomato were centrifuged, washed, and resuspended in phosphate-buffered saline (PBS) supplemented with 0.05% Tween 80 (PBS-T). Bacterial suspensions were then homogenized through a 26-gauge needle and sonicated, and the remaining clumps were allowed to settle down for 5 to 10 min. Bacteria were concentrated to an optical density at 600 nm (OD600) of 1 in PBS-T and injected intravenously (≈2 to 5 nl containing 50 to 300 CFU) into the caudal vein in 30-h-postfertilization (hpf) embryos previously dechorionated and anesthetized. To follow infection kinetics and embryo survival, infected larvae were transferred into 24-well plates (2 embryos/well) and incubated at 28.5°C. The CFU numbers in the inoculum were determined by injection of 2 nl of the bacterial suspension in sterile PBS-T and plating on 7H10 with 500 μg/ml hygromycin.

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Zebrafish Model of M. abscessus Infection: Zebrafish embryos (golden mutant crossed with wild-type AB) at 30 hours post-fertilization (hpf) were dechorionated and anesthetized. Rough M. abscessus CIP104536\(^T\) expressing the red fluorescent protein tdTomato was suspended in phosphate-buffered saline with 0.05% Tween 80 (PBS-T). Bacterial clumps were minimized by homogenization and brief sonication. Approximately 2-5 nl of the suspension (containing 50-300 CFU) was microinjected into the caudal vein of each embryo. After injection, infected larvae were transferred to 24-well plates (2 embryos/well) and incubated at 28.5°C. At 1 day post-infection (dpi), Bedaquiline was added directly to the water in the wells at final concentrations of 1, 2, or 3 µg/ml. The drug-containing water was replaced daily for the treatment duration (1, 2, or 3 days). Embryo survival was recorded daily for up to 13 dpi by checking for the absence of a heartbeat. The formation of abscesses and cords in live embryos was monitored and quantified using fluorescence and bright-field microscopy.[7]

Absorption, Distribution and Excretion
Following the recommended bedaquiline dosing regimen (400 mg for 2 weeks; followed by 200 mg three times weekly for 22 weeks), the calculated Cmax and AUC24h were 1.659 μg/ml and 25.863 μg·h/ml, respectively. Peak plasma concentration (Cmax) is typically reached approximately 5 hours after a single oral dose of bedaquiline. Cmax and the area under the plasma concentration-time curve (AUC) increase proportionally with increasing dose up to 700 mg (1.75 times the 400 mg loading dose). Compared to fasting, bedaquiline taken with a standard meal containing approximately 22 g of fat (558 kcal) increases relative bioavailability by approximately 2-fold. Bedaquiline should be taken with food to improve its oral bioavailability.
After reaching peak plasma concentration (Cmax), bedaquiline plasma concentrations exhibit a triple-exponential decline. Preclinical studies indicate that bedaquiline is primarily excreted in feces. In clinical studies, urinary excretion of unchanged bedaquiline was ≤0.001%, indicating negligible renal clearance of the unchanged drug.
The estimated volume of distribution of bedaquiline in the central compartment is approximately 164 liters.
The apparent clearance of bedaquiline is low, approximately 2.78 liters/hour.
Bedaquiline is a novel drug that can be used in combination with other drugs to treat multidrug-resistant Mycobacterium tuberculosis infection of the lungs. This study aimed to establish a population pharmacokinetic (PK) model of bedaquiline to describe drug concentration-time data from Phase I and Phase II clinical trials in healthy subjects and patients with drug-sensitive or multidrug-resistant tuberculosis (TB). A total of 5222 PK observations from 480 subjects were included and analyzed using a nonlinear mixed-effects model. The pharmacokinetic (PK) model employed a four-compartment distribution model, incorporating double zero-level injection (to capture the biphasic peaks observed during absorption) and a relatively long terminal half-life (t1/2). The model accounted for inter-subject variability in apparent clearance (CL/F), apparent central volume of distribution (Vc/F), dose fraction through the first injection port, and bioavailability (F). Bedaquiline has a wide distribution, a steady-state apparent volume of distribution >10,000 L, and low clearance. The long terminal half-life is likely due to drug redistribution from tissue compartments. The final covariate model adequately described the data and exhibited good simulation properties. Black subjects had a 52.0% higher CL/F than other racial groups, and women had a 15.7% lower Vc/F than men, although these differences were considered clinically insignificant in their impact on bedaquiline exposure. Minor differences in F and CL/F values existed between studies. The residual unexplained variability was 20.6%, with higher residual unexplained variability (27.7%) observed in long-term phase II studies. Bedaquiline is distributed in rat milk; it is unknown whether it is distributed in human milk. The plasma protein binding rate of bedaquiline is >99.9%. The estimated central compartment volume of distribution is approximately 164 liters. Following oral administration, the peak plasma concentration (Cmax) of bedaquiline is typically reached approximately 5 hours after administration. In healthy volunteers, both the peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) increased proportionally with increasing study dose (700 mg single dose and multiple daily doses of 400 mg). Compared to fasting, co-administration of bedaquiline with a standard meal containing approximately 22 grams of fat (558 kcal total energy) increases its relative bioavailability by approximately two-fold. Therefore, bedaquiline should be taken with food to improve its oral bioavailability. For more complete data on absorption, distribution, and excretion of bedaquiline (10 items in total), please visit the HSDB records page.

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Metabolism/Metabolites
CYP3A4 is the major CYP isoenzyme for the in vitro metabolism of bedaquiline and the formation of its N-monodemethyl metabolite (M2).
CYP3A4 is the major CYP isoenzyme for the in vitro metabolism of bedaquiline and the formation of its N-monodemethyl metabolite (M2). M2 has 4 to 6 times lower antimycobacterial activity than bedaquiline. Based on preclinical studies, bedaquiline is primarily excreted in feces. In clinical studies, urinary excretion of unchanged bedaquiline was less than 0.001% of the administered dose, indicating negligible renal clearance of the unchanged drug. Bedaquiline concentrations exhibit a tri-exponential decline after reaching peak concentration. The mean terminal elimination half-life of bedaquiline and its N-monodemethyl metabolite (M2) is approximately 5.5 months. This relatively long terminal elimination phase may reflect the slow release of bedaquiline and M2 from peripheral tissues.
In mice, after a single dose, the mean AUC_{0-24 hr} of the major metabolite M2 was 2 to 7 times higher than that of bedaquiline, while in rats and dogs, the AUC_{0-24 hr} of both was generally similar or 2 times lower.
Bedaquiline is a recently approved drug for the treatment of multidrug-resistant tuberculosis. Adverse cardiac and hepatic reactions have been observed with bedaquiline in clinical practice. This study used metabolomics to investigate the metabolism of bedaquiline in human hepatocytes. The study confirmed that CYP3A4-mediated N-demethylation of bedaquiline is the main metabolic pathway of bedaquiline. In addition to CYP3A4, we also found that CYP2C8 and CYP2C19 are involved in the N-demethylation of bedaquiline. The Km values for CYP2C8, CYP2C19, and CYP3A4 in the N-demethylation reaction of bedaquiline were 13.1 μM, 21.3 μM, and 8.5 μM, respectively. Furthermore, we discovered a novel metabolic pathway for bedaquiline that generates an aldehyde intermediate. In summary, this study expands our understanding of bedaquiline metabolism and can be used to predict and prevent drug interactions and adverse reactions associated with bedaquiline. No chiral conversion occurred after bedaquiline administration in mice, rats, dogs, monkeys, and humans. In hepatocytes and subcellular fractions of preclinical animals and humans, the in vitro metabolic pathway of 14C-bedaquiline is a phase I reaction, with the most important metabolic pathway being N-demethylation to M2, followed by a second N-demethylation to M3, as well as oxidation and epoxidation reactions. M2 was the major circulating metabolite in all preclinical animals, as determined by radiometric analysis and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Mass balance studies of radiolabeled bedaquiline in humans have not yet been conducted. Therefore, the possibility of generating metabolites undetectable in animals in humans cannot be ruled out. Following repeated administration of bedaquiline, the AUC0-24-hour concentration of M2 in rat and dog plasma was typically comparable to or 2-fold lower than that of bedaquiline, while it was 3.5 to 4.5-fold lower in patients with multidrug-resistant tuberculosis. In addition to M2 and M3, hydroxylated derivatives of M2 (M20) and dihydrodiol derivatives of M2 (M11) were also detected in human plasma. These two metabolites were also present at similar relative concentrations in rats and dogs.
Biological Half-Life
The mean terminal elimination half-life of bedaquiline and its N-monodemethylated metabolite (M2) is approximately 5.5 months.
This relatively long terminal elimination phase likely reflects the slow release of bedaquiline and M2 from peripheral tissues.
The plasma concentration-time curve of bedaquiline shows a multiphasic decrease with a long terminal elimination half-life of 2 to 3 days in mice, 3 to 5 days in male rats, 6 to 9 days in female rats and monkeys, and up to 50 days in dogs.
The mean terminal elimination half-life of bedaquiline and its N-monodemethyl metabolite (M2) is approximately 5.5 months.
This manuscript indicates that bedaquiline (TMC207, R207910) can easily cross the lipid bilayer, as demonstrated by its ability to rapidly alkalize E. coli liposomes and the interior of Mycobacterium bovis BCG cells without a pH gradient.
Specific pharmacokinetic parameters (e.g., absorption, distribution, metabolism, excretion, half-life, oral administration) are not provided in this paper for bioavailability. [2]

Toxicity Summary
Identification and Uses: Bedaquiline is a white solid used as an anti-tuberculosis drug. Human Exposure and Toxicity: In a placebo-controlled clinical trial, patients treated with bedaquiline had an increased risk of death. In this study, there were 9 deaths in the bedaquiline treatment group; one death occurred during the 24-week bedaquiline treatment period, and the median time to death for the remaining 8 patients was 329 days after the last dose. Five of the 9 deaths in the bedaquiline treatment group and two deaths in the placebo group were related to tuberculosis. The reasons for the imbalance in the number of deaths in this study are unclear; no correlation was found between death and sputum culture seroconversion, relapse, sensitivity to other anti-tuberculosis drugs, HIV infection status, or disease severity. Bedaquiline and its metabolite M2 are both cationic amphiphilic substances that can induce phospholipid deposition. Mononuclear phagocytes in all species are affected. In vitro human mononuclear cell line studies indicate that the M2 metabolite has the highest phospholipid-forming potential, followed by the M3 metabolite, and lastly the parent compound. Animal studies: Mice and rats experienced fatal symptoms following a single oral dose of 800 mg/kg, prior to prior systemic toxicity. Deaths in mice and dogs following single and repeated doses were primarily attributed to skeletal muscle/cardiac degeneration and/or pancreatitis. Bedaquinoline did not show carcinogenicity in rats, with a maximum tolerated dose of 10 mg/kg/day. In embryotoxicity studies in rats and rabbits, bedaquinoline appeared to have no adverse effects on embryonic development, with fetal variability and malformation rates within the normal range in the bedaquinoline group. Rats were exposed to a considerably high level of bedaquinoline and its metabolite M2 at high doses (6-7 times higher than expected human exposure), while the maximum exposure ratio in rabbits reached 2. However, in rabbits, a high dose of 100 mg/kg resulted in death, one abortion, and an increased rate of pre- and post-implantation embryo loss. At the highest tested dose of 24 mg/kg, bedaquinoline had no effect on female fertility. Male animals appeared to have decreased fertility, with a no-observed-adverse-effect level (NOAEL) of 5 mg/kg. No mutagenic or chromosome-breaking effects were detected in in vitro non-mammalian reverse mutation (Ames) assays, in vitro mammalian (mouse lymphoma) forward mutation assays, and in vivo mouse bone marrow micronucleus assays.

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Hepatotoxicity
In patients receiving multidrug combination therapy regimens containing bedaquiline, 8% to 12% experience abnormal liver function. These abnormalities are usually asymptomatic, mild to moderate in severity, and self-limiting. In many cases, it is difficult to determine which anti-tuberculosis drug caused these abnormalities, but monthly liver function monitoring is recommended during bedaquiline treatment. Clinically significant liver injury has been reported with bedaquiline treatment, but the clinical characteristics, course, and prognosis of these cases have not been described. At least three patients taking bedaquiline died from end-stage liver disease, but whether the liver failure was caused by bedaquiline remains in question. Treatment of multidrug-resistant tuberculosis is extremely challenging and should be guided by a physician experienced in treating tuberculosis.
Probability Score: E (Unproven but suspected cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Data from two women taking bedaquiline and their breastfed infants showed that the infants were exposed to a considerable amount of the drug through breast milk, with one infant reaching therapeutic serum drug concentrations. The clinical consequences of this exposure are unclear. The drug may protect infants from multidrug-resistant tuberculosis, but it may also cause adverse reactions. Breastfeeding should not be discontinued if the mother is taking bedaquiline. Monitor the breastfed infant for adverse reactions such as insufficient weight gain, hepatotoxicity, nausea, arthralgia, headache, hemoptysis, and chest pain.
◉ Effects on breastfed infants
A woman co-infected with HIV and rifampicin-resistant tuberculosis was taking bedaquiline (dosage not specified) as part of her anti-tuberculosis treatment regimen, which also included pyrazinamide and other unnamed drugs. At the one-month follow-up, the infant's weight was low and growth was poor, but the mother experienced nausea due to drug treatment and also experienced weight loss. Six months after the mother completed treatment, the infant's weight gain was normal, consistent with the growth curve, and developmental milestones were reached.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
Bedaquiline has a plasma protein binding rate greater than 99.9%.

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Interactions
Drug interactions (increased risk of QT interval prolongation). Concomitant use with other drugs that prolong the QT interval (e.g., clofazimine, fluoroquinolones, macrolides) may have additive or synergistic effects on the QT interval.
Bedaquiline is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. Concomitant use of bedaquiline with potent CYP3A4 inhibitors (such as ketoconazole) may increase the area under the concentration-time curve (AUC) of bedaquiline and increase the risk of drug-related adverse reactions. Unless the benefits outweigh the risks, concomitant use of bedaquiline with potent systemic CYP3A4 inhibitors should be avoided for more than 14 days. Patients receiving such concomitant therapy should be monitored for bedaquiline-related adverse reactions. Concomitant use of bedaquiline with potent CYP3A4 inducers (including rifamycins such as rifampin, rifapentine, and rifabutin) may decrease the AUC of bedaquiline and reduce its therapeutic effect. Concomitant use of bedaquiline with rifamycin or other potent CYP3A4 inducers should be avoided. Because concomitant use of bedaquiline with fluoroquinolones may increase the risk of QT interval prolongation, close electrocardiographic monitoring is necessary during concomitant therapy.
Because the co-administration of bedaquiline with macrolides may increase the risk of QT interval prolongation, electrocardiograms should be closely monitored during co-administration.
For more complete data on drug interactions of bedaquiline (13 items in total), please visit the HSDB record page.

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In the preliminary experiments, uninfected zebrafish embryos were exposed to increasing concentrations of bedaquiline and observed under a microscope. [7]

[1]. Bedaquiline susceptibility test for totally drug-resistant tuberculosis Mycobacterium tuberculosis. J Microbiol. 2017 Apr 20.

[2]. TBAJ-876 displays Bedaquiline-like mycobactericidal potency without retaining the parental drug's uncoupler activity. Antimicrob Agents Chemother. 2019 Nov 11.

[3]. Bedaquiline: a novel diarylquinoline for multidrug-resistant tuberculosis. Ann Pharmacother. 2014 Jan;48(1):107-15.

[4]. In Vitro Activity of Bedaquiline against Nontuberculous Mycobacteria in China. Antimicrob Agents Chemother. 2017 Apr 24;61(5).

[5]. Ann Pharmacother.2014 Jan;48(1):107-15.

[6]. Antimicrob Agents Chemother.2017 Apr 24;61(5). pii: e02627-16.
[7]. Antimicrob Agents Chemother. 2017 Nov; 61(11): e01225-17.

Therapeutic Uses

Anti-tuberculosis Drugs
Sirturo is a diarylquinoline anti-mycobacterial drug indicated for the combination therapy of multidrug-resistant tuberculosis (MDR-TB) in adults (≥18 years). Sirturo is intended only for cases where no other effective treatment is available. Sirturo should be administered under direct observation (DOT). This indication is based on an analysis of sputum culture clearance time in two phase II controlled trials in patients with MDR-TB. /US Product Label Includes/
The safety and efficacy of Sirturo in treating latent Mycobacterium tuberculosis infection have not been established. The safety and efficacy of Sirturo in treating drug-sensitive tuberculosis have not been established. Furthermore, there are no data on Sirturo for treating extrapulmonary tuberculosis (e.g., central nervous system tuberculosis). The safety and efficacy of Sirturo in treating nontuberculous mycobacterial (NTM) infections have not been established. Therefore, Sirturo is not recommended for use in these situations.
For over 40 years, a novel tuberculosis (TB) drug with a completely new mechanism of action—bedaquiline—has been introduced and received accelerated approval from the U.S. Food and Drug Administration (FDA) in December 2012. There is great interest in its potential to treat multidrug-resistant tuberculosis (MDR-TB). However, information about this new drug remains limited. It has only completed two Phase IIb safety and efficacy trials. Therefore, the World Health Organization (WHO) issued a “Interim Policy Guidance.” This interim guidance, based on the existing WHO guidelines for the management of drug-resistant tuberculosis (2011 updated), provides recommendations on how to incorporate bedaquiline into combination therapy for MDR-TB. The interim guidance lists five conditions that must be met when using bedaquiline to treat MDR-TB in adults: 1. Effective treatment and surveillance: A reasonable treatment and management regimen approved by the relevant national competent authority must be used, and the effectiveness and safety of treatment must be closely monitored. 2. Appropriate patient selection: Extra caution should be exercised when using bedaquiline in individuals aged 65 years and older and in adults infected with HIV. Use is not recommended in pregnant women and children. 3. Informed Consent: Patients must fully understand the potential benefits and risks of the new drug and sign an informed consent form before starting treatment. 4. Follow WHO Recommendations: All principles of the WHO-recommended treatment regimens for multidrug-resistant tuberculosis must be followed, especially the inclusion of four effective second-line drugs. According to general principles of tuberculosis treatment, bedaquiline should not be used alone if other drugs are ineffective. 5. Proactive Pharmacovigilance and Adverse Event Management: Proactive pharmacovigilance must be implemented to ensure early detection and proper management of adverse drug reactions and potential interactions with other drugs. The WHO strongly recommends accelerating the commencement of Phase III clinical trials to establish a more comprehensive evidence base to inform future policy development for bedaquiline. As more information regarding efficacy and safety becomes available, the WHO will review, revise, or update the interim guidelines.
Multidrug-resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis resistant to at least isoniazid and rifampin, two of the most effective of the four first-line anti-tuberculosis drugs (the other two being ethambutol and pyrazinamide). Multidrug-resistant tuberculosis (MDR-TB) includes a subtype called extensively drug-resistant tuberculosis (XDR-TB), which refers to tuberculosis that develops resistance to any fluoroquinolone drug and at least one injectable anti-tuberculosis drug (i.e., kanamycin, capreomycin, or amikacin) in addition to MDR-TB. MDR-TB is difficult to cure; even after sputum cultures become negative, treatment is still required for 18-24 months, with treatment regimens involving four to six drugs and often having toxic side effects. The risk of death is higher than in drug-sensitive tuberculosis. Bedaquiline fumarate (trade names: cetuximab or bedaquiline) is an oral diarylquinoline drug. On December 28, 2012, based on data from two Phase IIb clinical trials (i.e., rigorously controlled trials designed to evaluate the efficacy and safety of the drug in patients with a disease or condition to be treated, diagnosed, or prevented), the U.S. Food and Drug Administration (FDA) approved bedaquiline for “serious or life-threatening diseases” under the Accelerated Approval Regulation (21 CFR 314.500). …This report provides interim guidance from the U.S. Centers for Disease Control and Prevention (CDC) regarding FDA-approved and unapproved (or off-label) uses of bedaquiline in specific populations, such as children, pregnant women, or patients with extrapulmonary multidrug-resistant tuberculosis not included in clinical trials of the drug. These guidelines were developed by the CDC’s Division on Tuberculosis Elimination based on expert opinion and reference to systematic reviews and literature search data. This approach differs from the statutory standards used by the FDA in approving drugs and drug labeling. This guidance is intended to provide guidance to healthcare professionals who may use bedaquiline to treat multidrug-resistant tuberculosis (MDR-TB), including both indicated and unindicated use. This guidance does not contain all the same information as the currently approved bedaquiline package insert by the U.S. Food and Drug Administration (FDA). Bedaquiline should be used under the guidance of a clinical specialist as part of a combination therapy regimen (at least four drugs) and should be used under direct observation in adult patients aged 18 years and older diagnosed with pulmonary tuberculosis (MDR-TB) (FDA, Sirturo [Beddaquiline] Tablets Package Insert). When treatment options are limited, this drug may also be considered for individual patients in other categories (e.g., patients with extrapulmonary tuberculosis, children, pregnant women, or HIV-infected individuals or other comorbidities). However, further research is needed before recommending routine use of bedaquiline in these populations. A bedaquiline treatment patient registry is currently being established to track patient treatment outcomes, adverse reactions, laboratory test results (e.g., diagnosis, drug sensitivity, and development of resistance), concomitant medications, and other comorbidities. Suspected adverse reactions (i.e., any adverse event with a reasonable probability of being caused by the drug) and serious adverse events (i.e., any adverse event resulting in death) should be documented. Adverse consequences such as death, hospitalization, permanent disability, or life-threatening events should be reported…

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Drug Warning
/Black Box Warning/ Warning: In a placebo-controlled trial, the risk of death was higher in the Sirturo treatment group (9/79, 11.4%) than in the placebo treatment group (2/81, 2.5%). Sirturo should only be used when no other effective treatment is available. Sirturo can cause QT interval prolongation. Concomitant use with drugs that prolong the QT interval may result in additive QT interval prolongation.
Patients receiving bedaquiline-containing anti-tuberculosis regimens have a higher incidence of hepatic adverse events than those receiving bedaquiline-free regimens. Based on data from two clinical trials, 10.8% (5.7%) of patients receiving bedaquiline experienced reversible elevations in serum transaminase levels, reaching at least 3 times the upper limit of normal (ULN). Administer either bedaquiline or placebo. Liver function (AST, ALT, alkaline phosphatase, bilirubin) should be monitored at baseline, monthly during treatment, and as needed. Patients should also be monitored for signs of liver dysfunction. If new or worsening signs or symptoms of liver dysfunction appear (e.g., significantly elevated serum transaminases and/or bilirubin, fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly), the patient should be evaluated immediately. If AST or ALT is elevated more than 3 times the upper limit of normal, liver function tests should be repeated within 48 hours. In addition, the patient should be tested for viral hepatitis, and other hepatotoxic drugs should be discontinued. Bedaquiline should be discontinued if serum transaminase levels are elevated and total bilirubin levels are more than 2 times the upper limit of normal, or if serum transaminase levels are more than 8 times the upper limit of normal or elevated. Aminotransferase levels persist for more than 2 weeks. Patients taking bedaquiline should avoid alcohol and other hepatotoxic drugs or herbal products, especially those with impaired liver reserve.
Patients taking bedaquiline have experienced QT interval prolongation. Bedaquiline may have an additive or synergistic effect on QT interval when used in combination with other drugs that prolong the QT interval. To date, there have been no reported cases of torsades de pointes in patients taking bedaquiline. The safety and efficacy of bedaquiline in patients under 18 years of age have not been established. For more complete data on bedaquiline warnings (10 in total), please visit the HSDB record page.

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Pharmacodynamics
Bedaquiline is primarily metabolized oxidatively to produce the N-monodemethyl metabolite (M2). M2 is considered to have little clinical impact. Its efficacy remains to be improved given its low average human exposure (23% to 31%) and lower antimycobacterial activity than the parent compound (4 to 6 times lower). However, plasma concentrations of M2 appear to be associated with QT interval prolongation. The minimum inhibitory concentration (MIC) of bedaquiline against Mycobacterium tuberculosis is 0.002–0.06 μg/ml, with a MIC50 of 0.03 μg/ml. The proportion of naturally resistant bacteria is low, estimated at only one strain per 10⁷/10⁸ bacteria. Bacteria with lower ATP reserves (e.g., dormant, non-replicating bacilli) are more sensitive to bedaquiline. Furthermore, bedaquiline is also effective against non-tuberculous mycobacteria, with MICs ranging from 0.06 to 0.5 μg/ml. The possibility of developing resistance exists. Bedaquiline resistance exists in Mycobacterium tuberculosis. Modification of the atpE target gene and/or upregulation of the MmpS5-MmpL5 efflux pump (Rv0678 mutation) are associated with increased bedaquiline MICs in Mycobacterium tuberculosis isolates. Mutations in the target gene generated in preclinical studies resulted in an 8- to 133-fold increase in the MIC value of bedaquiline, ranging from 0.25 to 4 μg/mL. Efflux pump mutations were observed in both preclinical and clinical isolates. These mutations resulted in a 2- to 8-fold increase in the MIC value of bedaquiline, ranging from 0.25 to 0.5 μg/mL.

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Bedaquiline (TMC207, R207910) is a diarylquinoline drug used to treat multidrug-resistant tuberculosis. Tuberculosis.
It has a dual mechanism of action: firstly, it inhibits mycobacterial F1F0-ATP synthase, and secondly, it acts as a proton carrier to uncouple oxidative phosphorylation.
Uncoupling activity is thought to contribute to its bactericidal effect, but this study, compared with the analog TBAJ-876, suggests that it may not be a necessary condition for potent bactericidal activity.
The proton carrier activity of this drug is affected by its lipophilicity and respiratory electron donor.
[2]

C32H31BRN2O2

555.5

554.16

C, 69.19; H, 5.62; Br, 14.38; N, 5.04; O, 5.76

843663-66-1

Bedaquiline fumarate;845533-86-0;(Rac)-Bedaquiline;654655-80-8;(Rac)-Bedaquiline-d6;2517573-53-2;Bedaquiline impurity 2-d6

5388906

White to yellow solid powder

1.3±0.1 g/cm3

702.7±60.0 °C at 760 mmHg

118 °C

378.8±32.9 °C

0.0±2.3 mmHg at 25°C

1.666

7.59

1

4

8

37

715

2

[C@](C1C=CC=C2C=CC=CC=12)(O)(CCN(C)C)[C@H](C1C=CC=CC=1)C1C=C2C=C(C=CC2=NC=1OC)Br

QUIJNHUBAXPXFS-XLJNKUFUSA-N

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

(1R,2S)-1-(6-Bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol

R207910; TMC207; R-207910; TMC-207; R 207910; TMC 207; Bedaquiline; Bedaquiline fumarate; trade name: Sirturo; AIDS-222089; bedaquilina;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 12.5~33 mg/mL ( 22.50~59.4 mM )

Solubility in Formulation 1: ≥ 0.5 mg/mL (0.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 0.5 mg/mL (0.90 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 0.5 mg/mL (0.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly..

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Solubility in Formulation 4: Solubility in Formulation 1: ≥ 0.5 mg/mL (0.9 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can take 100 μL of 5 mg/mL DMSO stock solution and add to 400 μL of PEG300, mix well (clear solution); Then add 50 μL of Tween 80 to the above solution, mix well (clear solution); Finally, add 450 μL of saline to the above solution, mix well (clear solution).
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)