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Bedaquiline (TMC-207; R-207910; TMC207; R207910; Sirturo) is a potent and orally bioavailable medication approved to treat active TB/tuberculosis. It is structurally a diarylquinoline that inhibits mycobacterial ATP synthase. Bedaquiline is specifically used to treat multi-drug-resistant tuberculosis (MDR-TB) when other treatments cannot be used. It should be used along with at least three other medications for tuberculosis. 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 most effective and safe medicines needed in a health system. The cost for six months is approximately $900 USD in low income countries, $3,000 USD in middle income countries, and $30,000 USD in high income countries.
Physicochemical Properties
| Molecular Formula | C32H31BRN2O2 |
| Molecular Weight | 555.5 |
| Exact Mass | 554.16 |
| Elemental Analysis | C, 69.19; H, 5.62; Br, 14.38; N, 5.04; O, 5.76 |
| CAS # | 843663-66-1 |
| Related CAS # | Bedaquiline fumarate;845533-86-0;(Rac)-Bedaquiline;654655-80-8;(Rac)-Bedaquiline-d6;2517573-53-2;Bedaquiline impurity 2-d6 |
| PubChem CID | 5388906 |
| Appearance | White to yellow solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 702.7±60.0 °C at 760 mmHg |
| Melting Point | 118 °C |
| Flash Point | 378.8±32.9 °C |
| Vapour Pressure | 0.0±2.3 mmHg at 25°C |
| Index of Refraction | 1.666 |
| LogP | 7.59 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 37 |
| Complexity | 715 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | [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 |
| InChi Key | QUIJNHUBAXPXFS-XLJNKUFUSA-N |
| InChi Code | 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 |
| Chemical Name | (1R,2S)-1-(6-Bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol |
| Synonyms | R207910; TMC207; R-207910; TMC-207; R 207910; TMC 207; Bedaquiline; Bedaquiline fumarate; trade name: Sirturo; AIDS-222089; bedaquilina; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Mtb F1FO-ATP synthase |
| ln Vitro |
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]. |
| ln Vivo | 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] |
| Enzyme Assay |
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] |
| Cell Assay |
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. |
| Animal Protocol |
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. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion After the recommended dosing regimen of bedaquiline (400 mg for 2 weeks followed by 200 mg three times per week for 22 weeks), the Cmax and AUC24h were calculated to be 1.659 μg/ml and 25.863 μg.h/ml respectively. After a single oral dose administration of bedaquiline, maximum plasma concentrations (Cmax) are typically achieved at approximately 5 hours post-dose. Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally up to 700 mg (1.75 times the 400 mg loading dose). Administration of bedaquiline with a standard meal containing approximately 22 grams of fat (558 total Kcal) increased the relative bioavailability by approximately 2-fold compared to administration under fasted conditions. Bedaquiline should be taken with food to enhance its oral bioavailability. After reaching Cmax, bedaquiline concentrations decline tri-exponentially. Based on preclinical studies, bedaquiline is mainly excreted in feces. The urinary excretion of unchanged bedaquiline was less than or equal to 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant. The volume of distribution in the central compartment is estimated to be approximately 164 Liters. Bedaquiline has a low apparent clearance of approximately 2.78 L/h. Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and Vc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies. Bedaquiline is distributed into milk in rats; it is not known whether the drug is distributed into human milk. The plasma protein binding of bedaquiline is > 99.9%. The volume of distribution in the central compartment is estimated to be approximately 164 L. After oral administration bedaquiline maximum plasma concentrations (Cmax) are typically achieved at approximately 5 hours post-dose. Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally up to the highest doses studied in healthy volunteers (700 mg single-dose and once daily 400 multiple doses). Administration of bedaquiline with a standard meal containing approximately 22 grams of fat (558 total Kcal) increased the relative bioavailability by about 2-fold compared to administration under fasted conditions. Therefore, bedaquiline should be taken with food to enhance its oral bioavailability. For more Absorption, Distribution and Excretion (Complete) data for Bedaquiline (10 total), please visit the HSDB record page. Metabolism / Metabolites CYP3A4 was the major CYP isoenzyme involved in the in vitro metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2). CYP3A4 was the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2), which is 4 to 6-times less active in terms of antimycobacterial potency. Based on preclinical studies, bedaquiline is mainly eliminated in feces. The urinary excretion of unchanged bedaquiline was < 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant. After reaching Cmax, bedaquiline concentrations decline tri-exponentially. The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months. This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from peripheral tissues. After a single dose the mean AUC0-24 hr of the major metabolite M2 was 2 to 7-fold higher than AUC0-24 hr of bedaquiline in mice and was generally similar to 2-fold lower in rats and dogs. Bedaquiline is a recently approved drug for the treatment of multidrug-resistant tuberculosis. Adverse cardiac and hepatic drug reactions to bedaquiline have been noted in clinical practice. The current study investigated bedaquiline metabolism in human hepatocytes using a metabolomic approach. Bedaquiline N-demethylation via CYP3A4 was confirmed as the major pathway in bedaquiline metabolism. In addition to CYP3A4, we found that both CYP2C8 and CYP2C19 contributed to bedaquiline N-demethylation. The Km values of CYP2C8, CYP2C19, and CYP3A4 in bedaquiline N-demethylation were 13.1, 21.3, and 8.5 uM, respectively. We also identified a novel metabolic pathway of bedaquiline that produced an aldehyde intermediate. In summary, this study extended our knowledge of bedaquiline metabolism, which can be applied to predict and prevent drug-drug interactions and adverse drug reactions associated with bedaquiline. No chiral conversion of bedaquiline occurred in vivo after administration of bedaquiline to mice, rats, dogs, monkeys and humans. In hepatocytes and subcellular fractions from preclinical species and humans, the in vitro metabolism of (14)C-bedaquiline was via Phase I reactions and the most important pathway was N-demethylation to M2, which was followed by a second N-demethylation to M3, oxidation and epoxidation. M2 was the major circulating metabolite in all preclinical species as determined by radioactivity profiling and LC-MS/MS in the animals. No mass balance study with radiolabelled bedaquiline has been conducted in humans. It can therefore not be excluded that additional undetected metabolites may be formed in humans that are not formed in the animal species. M2-AUC0-24 hr plasma levels were generally comparable to 2-fold lower than those of bedaquiline in rats and dogs upon repeated administration of bedaquiline, and 3.5- to 4.5-fold lower in human subjects with MDR-TB. In addition to M2 and M3, a hydroxylated derivative of M2 (M20) and a dihydrodiol derivative of M2 (M11), were detected in human plasma. These two metabolites were also found in rats and dogs at similar relative concentrations. Biological Half-Life The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months. This long terminal elimination phase likely reflects the slow release of bedaquiline and M2 from peripheral tissues. The plasma concentration-time profiles of bedaquiline showed a multi-phasic decline with a long terminal elimination half life ranging from 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 the N-monodesmethyl metabolite (M2) is approximately 5.5 months. |
| Toxicity/Toxicokinetics |
Toxicity Summary IDENTIFICATION AND USE: Bedaquiline is a white solid. It is used as a antitubercular medication. HUMAN EXPOSURE AND TOXICITY: An increased risk of death was observed in patients receiving bedaquiline in a placebo-controlled clinical trial. In this study, there were 9 deaths in bedaquiline-treated patients; one death occurred during the 24 weeks of bedaquiline therapy and the median time to death for the other 8 patients was 329 days after the last dose of bedaquiline. Five of the 9 deaths in bedaquiline-treated patients and both deaths in placebo-treated patients were related to tuberculosis. The explanation for the imbalance in deaths in this study is not known; no correlation was demonstrated between death and sputum culture conversion, relapse, susceptibility to other antituberculosis drugs, HIV status, or disease severity. Bedaquiline and the M2 metabolite are cationic amphiphilic substances and induce phospholipidosis. The cells of the monocytic phagocytic system are affected in all species. Data from in vitro studies using human monocyte cell-line indicated that the phospholipidogenic potential was highest for the M2 metabolite followed by M3 and the parent compound. ANIMAL STUDIES: In mouse and rat, single oral doses of 800 mg/kg produced lethality preceded by signs of general toxicity. Mortalities in mouse and dog after single and repeated doses were principally attributed to skeletal muscle/myocardial degeneration and/or pancreatitis. Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. In embryofetal toxicity studies conducted in rat and rabbit bedaquiline appeared to have no adverse effects on the embryonal development and the incidence of variations and malformations in fetuses in bedaquiline groups were within normal ranges. Exposure to bedaquiline and the M2 metabolite in rat at the high dose was considerable (up to 6-7 times higher compared with expected human exposure), while in rabbit a maximum exposure ratio of 2 were achieved. However, in rabbit the high dose of 100 mg/kg caused deaths, one abortion and increases in pre and postimplantation losses. Bedaquiline had no effect on fertility in females up to the highest dose tested, 24 mg/kg. Male fertility appeared to be decreased with a NOAEL of 5 mg/kg. No mutagenic or clastogenic effects were detected in the in vitro non-mammalian reverse mutation (Ames) test, in vitro mammalian (mouse lymphoma) forward mutation assay and an in vivo mouse bone marrow micronucleus assay. Hepatotoxicity Liver test abnormalities occur in 8% to 12% of patients treated with multiple drug regimens that include bedaquiline. These abnormalities are usually asymptomatic, mild-to-moderate in severity and self-limited in duration. In many instances, it is difficult to determine which of the antituberculosis medications accounts for the abnormalities, but monitoring of liver tests at monthly intervals is recommended during bedaquiline therapy. Clinically apparent liver injury has been reported with bedaquiline therapy, but the clinical features, course and outcome of these cases has not been described. At least three deaths from end stage liver disease have been described in patients taking bedaquiline, but the attribution of the hepatic failure to bedaquiline has been questioned. The management of multidrug resistant tuberculosis is challenging and should be under the direction of physicians with expertise in tuberculosis therapy. Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Data from two women taking bedaquiline and one of their breastfed infants indicate that exposure of the infant to the drug via breastmilk is substantial, with one infant having a therapeutic serum level. The clinical consequences of this exposure are unknown. The drug could protect the infant from multidrug-resistant tuberculosis, or could result in adverse effects. If bedaquiline is required by the mother, it is not a reason to discontinue breastfeeding. Monitor breastfed infants for adverse reactions, such as inadequate weight gain, liver toxicity, nausea, arthralgia, headache, hemoptysis, and chest pain. ◉ Effects in Breastfed Infants A woman who was co-infected with HIV and rifampin-resistant tuberculosis took bedaquiline (dosage not stated) as part of her antituberculosis regimen, which consisted of pyrazinamide and other unnamed drugs. At the 1-month follow-up, the infant was small and not gaining weight well, but the mother was nauseated from her medication regimen and had also lost weight. Six months later after completion of the mother’s therapy, her infant’s weight was increasing, following the normal trajectory of the growth chart, and reaching her developmental milestones. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding The plasma protein binding of bedaquiline is greater than 99.9%. Interactions Pharmacologic interaction (increased risk of QT interval prolongation). Concomitant use with other drugs that prolong the QT interval (e.g., clofazimine, fluoroquinolones, macrolides) may result in additive or synergistic effects on the QT interval. Bedaquiline is metabolized primarily by cytochrome P-450 (CYP) isoenzyme 3A4. Concomitant use of bedaquiline with potent inhibitors of CYP3A4 (e.g., ketoconazole) may increase the area under the concentration-time curve (AUC) of bedaquiline and increase the risk of adverse effects associated with the drug. Concomitant use of bedaquiline and systemic drugs that are potent inhibitors of CYP3A4 for a duration longer than 14 consecutive days should be avoided, unless the benefits of concomitant use outweigh the risks. Patients receiving such concomitant therapy should be monitored for bedaquiline-related adverse effects. Concomitant use of bedaquiline with potent inducers of CYP3A4, including rifamycins (e.g., rifampin, rifapentine, rifabutin), may reduce the AUC of bedaquiline and decrease the therapeutic effects of the drug. Concomitant use of bedaquiline with rifamycins or other potent inducers of CYP3A4 should be avoided. Because concomitant use of bedaquiline and fluoroquinolones may increase the risk of QT interval prolongation, ECGs should be monitored closely during concomitant therapy. Because concomitant use of bedaquiline and macrolides may increase the risk of QT interval prolongation, ECGs should be monitored closely during concomitant therapy. For more Interactions (Complete) data for Bedaquiline (13 total), please visit the HSDB record page. |
| References |
[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. |
| Additional Infomation |
Therapeutic Uses Antitubercular Agents Sirturo is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (= 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve Sirturo for use when an effective treatment regimen cannot otherwise be provided. Sirturo should be administered by directly observed therapy (DOT). This indication is based on analysis of time to sputum culture conversion from two controlled Phase 2 trials in patients with pulmonary MDR-TB. /Included in US product label/ The safety and efficacy of Sirturo for the treatment of latent infection due to Mycobacterium tuberculosis have not been established. The safety and efficacy of Sirturo for the treatment of drug-sensitive TB have not been established. In addition, there are no data on the treatment with Sirturo of extra-pulmonary TB (e.g., central nervous system). The safety and efficacy of Sirturo for the treatment of infections caused by non-tuberculous mycobacteria (NTM) have not been established. Therefore, use of SIRTURO in these settings is not recommended. For the first time in over 40 years, a new tuberculosis (TB) drug with a novel mechanism of action - bedaquiline - is available, and was granted accelerated approval by the United States Food and Drug Administration in December 2012. There is considerable interest in the potential of this drug to treat multidrug-resistant tuberculosis (MDR-TB). However, information about this new drug remains limited. It has only been through two Phase IIb trials for safety and efficacy. WHO is therefore issuing "interim policy guidance". This interim guidance provides advice on the inclusion of bedaquiline in the combination therapy of MDR-TB in accordance with the existing WHO Guidelines for the programmatic management of drug-resistant TB (2011 Update). The interim guidance lists five conditions that must be in place if bedaquiline is used to treat adults with MDR-TB: 1.Effective treatment and monitoring: Treatment must be closely monitored for effectiveness and safety, using sound treatment and management protocols approved by relevant national authorities. 2.Proper patient inclusion: Special caution is required when bedaquiline is used in people aged 65 and over, and in adults living with HIV. Use in pregnant women and children is not advised. 3.Informed consent: Patients must be fully aware of the potential benefits and harms of the new drug, and give documented informed consent before embarking on treatment. 4.Adherence to WHO recommendations: All principles on which WHO-recommended MDR-TB treatment regimens are based, must be followed, particularly the inclusion of four effective second-line drugs. In line with general principles of TB therapeutics, bedaquiline alone should not be introduced into a regimen in which the companion drugs are failing to show effectiveness. 5.Active pharmacovigilance and management of adverse events: Active pharmacovigilance measures must be in place to ensure early detection and proper management of adverse drug reactions and potential interactions with other drugs. WHO strongly recommends the acceleration of Phase III trials to generate a more comprehensive evidence base to inform future policy on bedaquiline. The Organization will review, revise, or update the interim guidance as additional information on efficacy and safety become available. Multidrug-resistant tuberculosis (MDR TB) is caused by Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampin, the two most effective of the four first-line TB drugs (the other two drugs being ethambutol and pyrazinamide). MDR TB includes the subcategory of extensively drug-resistant TB (XDR TB), which is MDR TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, capreomycin, or amikacin). MDR TB is difficult to cure, requiring 18-24 months of treatment after sputum culture conversion with a regimen that consists of four to six medications with toxic side effects, and carries a mortality risk greater than that of drug-susceptible TB. Bedaquiline fumarate (Sirturo or bedaquiline) is an oral diarylquinoline. On December 28, 2012, on the basis of data from two Phase IIb trials (i.e., well-controlled trials to evaluate the efficacy and safety of drugs in patients with a disease or condition to be treated, diagnosed, or prevented), the Food and Drug Administration (FDA) approved use of bedaquiline under the provisions of the accelerated approval regulations for "serious or life-threatening illnesses" (21CFR314.500). ... This report provides provisional CDC guidelines for FDA-approved and unapproved, or off-label, uses of bedaquiline in certain populations, such as children, pregnant women, or persons with extrapulmonary MDR TB who were not included in the clinical trials for the drug. CDC's Division of TB Elimination developed these guidelines on the basis of expert opinion informed by data from systematic reviews and literature searches. This approach is different from the statutory standards that FDA uses when approving drugs and drug labeling. These guidelines are intended for health-care professionals who might use bedaquiline for the treatment of MDR TB for indicated and off-label uses. Aspects of these guidelines are not identical to current FDA-approved labeling for bedaquiline. Bedaquiline should be used with clinical expert consultation as part of combination therapy (minimum four-drug treatment regimen) and administered by direct observation to adults aged =18 years with a diagnosis of pulmonary MDR TB (Food and Drug Administration. Sirturo [bedaquiline] tablets label. ... Use of the drug also can be considered for individual patients in other categories (e.g., persons with extrapulmonary TB, children, pregnant women, or persons with HIV or other comorbid conditions) when treatment options are limited. However, further study is required before routine use of bedaquiline can be recommended in these populations. A registry for persons treated with bedaquiline is being implemented by ... to track patient outcomes, adverse reactions, laboratory testing results (e.g., diagnosis, drug susceptibility, and development of drug resistance), use of concomitant medications, and presence of other comorbid conditions. Suspected adverse reactions (i.e., any adverse event for which there is a reasonable possibility that the drug caused the adverse event) and serious adverse events (i.e., any adverse event that results in an outcome such as death, hospitalization, permanent disability, or a life-threatening situation) should be reported ... . Drug Warnings /BOXED WARNING/ WARNINGS: An increased risk of death was seen in the Sirturo treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial. Only use Sirturo when an effective treatment regimen cannot otherwise be provided. QT prolongation can occur with Sirturo. Use with drugs that prolong the QT interval may cause additive QT prolongation. A higher incidence of adverse hepatic effects has been reported in patients receiving antituberculosis regimens containing bedaquiline compared with patients receiving regimens that did not contain the drug. Based on data from 2 clinical trials, reversible increases in serum aminotransferase concentrations to at least 3 times the upper limit of normal (ULN) were reported in 10.8 or 5.7% of patients receiving bedaquiline or placebo, respectively. Liver function tests (AST, ALT, alkaline phosphatase, bilirubin) should be monitored at baseline, monthly during treatment, and as needed. Patients also should be monitored for symptoms of hepatic dysfunction. If signs or symptoms of new or worsening liver dysfunction (e.g., clinically important elevation in serum aminotransferases and/or bilirubin, fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) develop, the patient should be promptly evaluated. If AST or ALT increase to greater than 3 times the ULN, liver function tests should be repeated within 48 hours. In addition, patients should be tested for viral hepatitis and other hepatotoxic drugs should be discontinued. Bedaquiline should be discontinued if elevated serum aminotransferase concentrations are accompanied by total bilirubin concentrations exceeding 2 times the ULN, serum aminotransferase concentrations exceed 8 times the ULN, or elevated aminotransferase concentrations persist for more than 2 weeks. Alcohol and other hepatotoxic drugs or herbal products should be avoided in patients receiving bedaquiline, especially in those with diminished hepatic reserve. Prolongation of the QT interval has occurred in patients receiving bedaquiline. Concomitant use of bedaquiline with other drugs associated with QT interval prolongation may result in additive or synergistic effects on the QT interval. Documented cases of torsades de pointes have not been reported to date in patients receiving bedaquiline. Safety and efficacy of bedaquiline have not been established in patients younger than 18 years of age. For more Drug Warnings (Complete) data for Bedaquiline (10 total), please visit the HSDB record page. Pharmacodynamics Bedaquiline is primarily subjected to oxidative metabolism leading to the formation of N-monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (4-fold to 6-fold lower) than the parent compound. However, M2 plasma concentrations appeared to correlate with QT prolongation. Bedaquiline inhibits mycobacterial TB at a minimal inhibitory concentration (MIC) from 0.002-0.06 μg/ml and with a MIC50 of 0.03 μg/ml. The proportion of naturally resistant bacteria is low, estimated to be in one strain over 107/108 bacteria. Bacteria that have smaller ATP stores (such as dormant, nonreplicating bacilli) are more susceptible to bedaquiline. Additionally, bedaquiline is also effective against nontuberculous mycobacteria, with MICs ranging from 0.06 to 0.5 μg/ml. A potential for the development of resistance to bedaquiline in M. tuberculosis exists. Modification of the atpE target gene, and/or upregulation of the MmpS5-MmpL5 efflux pump (Rv0678 mutations) have been associated with increased bedaquiline MIC values in isolates of M. tuberculosis. Target-based mutations generated in preclinical studies lead to 8- to 133-fold increases in bedaquiline MIC, resulting in MICs ranging from 0.25 to 4 micrograms per mL. Efflux-based mutations have been seen in preclinical and clinical isolates. These lead to 2- to 8-fold increases in bedaquiline MICs, resulting in bedaquiline MICs ranging from 0.25 to 0.5 micrograms per mL. |
Solubility Data
| Solubility (In Vitro) | DMSO : 12.5~33 mg/mL ( 22.50~59.4 mM ) |
| Solubility (In Vivo) |
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. 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. 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.. 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. Solubility in Formulation 2: 0.5 mg/mL (0.9 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD in saline, mix well (clear solution). 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. Solubility in Formulation 3: 0.5 mg/mL (0.9 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 take 100 μL of 5 mg/mL DMSO stock solution and add to 900 μL of corn oil, mix well (clear solution). Solubility in Formulation 4: 1.67mg/ml (3.01mM) in 5% DMSO + 95% Corn oil (add these co-solvents sequentially from left to right, and one by one), clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8002 mL | 9.0009 mL | 18.0018 mL | |
| 5 mM | 0.3600 mL | 1.8002 mL | 3.6004 mL | |
| 10 mM | 0.1800 mL | 0.9001 mL | 1.8002 mL |