Identification
- Summary
Bedaquiline is a diarylquinoline antimycobacterial used in combination with other antibacterials to treat pulmonary multidrug resistant tuberculosis (MDR-TB).
- Brand Names
- Sirturo
- Generic Name
- Bedaquiline
- DrugBank Accession Number
- DB08903
- Background
Bedaquiline is a bactericidal antimycobacterial drug belonging to the class of diarylquinoline. The quinolinic central heterocyclic nucleus with alcohol and amine side chains is responsible for bedaquiline-mediated antimycobacterial activity.5 Although it is closely related to fluoroquinolones, bedaquiline does not affect DNA gyrase; instead, bedaquiline inhibits the c subunit of ATP synthase responsible for synthesizing ATP.5 Consequently, bedaquiline can be used to treat mycobacterial infection, particularly tuberculosis (TB).6 Although the current standard of TB treatment of anti-TB drugs for 2 months, including 2 key drugs isoniazid and rifampin, is highly effective, the emergence of multidrug-resistant TB (MDR-TB) to isoniazid and rifampin has substantially worsened patients outcome.4
Bedaquiline was approved by the FDA on December 28, 2012, to treat pulmonary MDR-TB, following favorable results in multiple pre-clinical and clinical studies.3,4 It is the first drug that was approved in the last 40 years by the FDA for TB unresponsive to current treatments on the market.3 Currently, bedaquiline is the last-line anti-TB drug and must only be used in an appropriate combination regimen.6,5
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Bedaquiline (DB08903)
- Weight
- Average: 555.505
Monoisotopic: 554.156890893 - Chemical Formula
- C32H31BrN2O2
- Synonyms
- 1-(6-Bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol
- Bedaquilina
- Bedaquiline
- Bédaquiline
- Bedaquilinum
- External IDs
- AIDS222089
- R 207910
- R-207910
- R207910
- TMC 207
- TMC-207
- TMC207
Pharmacology
- Indication
Bedaquiline is indicated as part of combination therapy in the treatment of adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided.6
This indication is approved under FDA accelerated approval based on time to sputum culture conversion. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.6
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Pulmonary multi-drug resistant tuberculosis (mdr-tb) •••••••••••• •••••• ••••••••• •••• •••••• •• •• ••••• •• •• •••••• - Contraindications & Blackbox Warnings
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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.6
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.1
Additionally, bedaquiline is also effective against nontuberculous mycobacteria, with MICs ranging from 0.06 to 0.5 μg/ml.1
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.6
- Mechanism of action
Bedaquiline is a diarylquinoline antimycobacterial drug that inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, by binding to subunit c of the enzyme that is essential for the generation of energy in M. tuberculosis..6
Target Actions Organism AATP synthase subunit c inhibitorMycobacterium tuberculosis - Absorption
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.6
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).6
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.6
- Volume of distribution
The volume of distribution in the central compartment is estimated to be approximately 164 Liters.6
- Protein binding
The plasma protein binding of bedaquiline is greater than 99.9%.6
- Metabolism
CYP3A4 was the major CYP isoenzyme involved in the in vitro metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2).6
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- Route of elimination
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.6
- 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.6
- Clearance
Bedaquiline has a low apparent clearance of approximately 2.78 L/h.2
- Adverse Effects
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There is no experience with the treatment of acute overdose with SIRTURO. Take general measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) in case of deliberate or accidental overdose. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma.6
Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. Exposures at this dose in rats (AUCs) were within 1-fold to 2-fold of those observed in adult patients in the clinical trials.6
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.6
SIRTURO did not affect fertility when evaluated in male and female rats at approximately twice the clinical exposure based on AUC comparisons. There was no effect of maternal treatment on sexual maturation, mating performance, or fertility in the F1 generation exposed to bedaquiline in utero at approximately twice the human exposure.6
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Bedaquiline can be increased when it is combined with Abametapir. Acebutolol The risk or severity of QTc prolongation can be increased when Acebutolol is combined with Bedaquiline. Acenocoumarol The risk or severity of bleeding can be increased when Bedaquiline is combined with Acenocoumarol. Acrivastine The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Bedaquiline. Adagrasib The risk or severity of QTc prolongation can be increased when Adagrasib is combined with Bedaquiline. - Food Interactions
- Avoid alcohol.
- Take with food. Food significantly increases the oral bioavailability.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Bedaquiline fumarate P04QX2C1A5 845533-86-0 ZLVSPMRFRHMMOY-WWCCMVHESA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Sirturo Tablet 100 mg Oral Janssen Cilag International Nv 2016-09-08 Not applicable EU 
Sirturo Tablet 20 mg Oral Janssen Cilag International Nv 2022-05-04 Not applicable EU Sirturo Tablet 100 mg/1 Oral Janssen Products, LP 2012-12-28 Not applicable US 
Sirturo Tablet 100 mg Oral Janssen Cilag International Nv 2016-09-08 Not applicable EU Sirturo Tablet 20 mg/1 Oral Janssen Products, LP 2020-05-27 Not applicable US
Categories
- ATC Codes
- J04AK05 — Bedaquiline
- Drug Categories
- Anti-Bacterial Agents
- Anti-Infective Agents
- Antiinfectives for Systemic Use
- Antimycobacterials
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Diarylquinoline Antimycobacterial
- Drugs for Treatment of Tuberculosis
- Heterocyclic Compounds, Fused-Ring
- Moderate Risk QTc-Prolonging Agents
- QTc Prolonging Agents
- Quinolines
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
- Kingdom
- Organic compounds
- Super Class
- Phenylpropanoids and polyketides
- Class
- Stilbenes
- Sub Class
- Not Available
- Direct Parent
- Stilbenes
- Alternative Parents
- Quinolones and derivatives / Haloquinolines / Phenylbutylamines / Naphthalenes / Alkyl aryl ethers / Aralkylamines / Aryl bromides / Pyridines and derivatives / Heteroaromatic compounds / 1,3-aminoalcohols show 7 more
- Substituents
- 1,3-aminoalcohol / Alcohol / Alkyl aryl ether / Amine / Aralkylamine / Aromatic alcohol / Aromatic heteropolycyclic compound / Aryl bromide / Aryl halide / Azacycle show 23 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- tertiary alcohol, organobromine compound, tertiary amino compound, aromatic ether, quinolines, naphthalenes (CHEBI:72292)
- Affected organisms
- Mycobacterium tuberculosis
Chemical Identifiers
- UNII
- 78846I289Y
- CAS number
- 843663-66-1
- InChI Key
- QUIJNHUBAXPXFS-XLJNKUFUSA-N
- InChI
- 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
- IUPAC Name
- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
- SMILES
- COC1=NC2=C(C=C(Br)C=C2)C=C1[C@@H](C1=CC=CC=C1)[C@@](O)(CCN(C)C)C1=CC=CC2=C1C=CC=C2
References
- General References
- Matteelli A, Carvalho AC, Dooley KE, Kritski A: TMC207: the first compound of a new class of potent anti-tuberculosis drugs. Future Microbiol. 2010 Jun;5(6):849-58. doi: 10.2217/fmb.10.50. [Article]
- McLeay SC, Vis P, van Heeswijk RP, Green B: Population pharmacokinetics of bedaquiline (TMC207), a novel antituberculosis drug. Antimicrob Agents Chemother. 2014 Sep;58(9):5315-24. doi: 10.1128/AAC.01418-13. Epub 2014 Jun 23. [Article]
- Mahajan R: Bedaquiline: First FDA-approved tuberculosis drug in 40 years. Int J Appl Basic Med Res. 2013 Jan;3(1):1-2. doi: 10.4103/2229-516X.112228. [Article]
- Fox GJ, Menzies D: A Review of the Evidence for Using Bedaquiline (TMC207) to Treat Multi-Drug Resistant Tuberculosis. Infect Dis Ther. 2013 Dec;2(2):123-44. doi: 10.1007/s40121-013-0009-3. Epub 2013 Aug 2. [Article]
- Khoshnood S, Goudarzi M, Taki E, Darbandi A, Kouhsari E, Heidary M, Motahar M, Moradi M, Bazyar H: Bedaquiline: Current status and future perspectives. J Glob Antimicrob Resist. 2021 Jun;25:48-59. doi: 10.1016/j.jgar.2021.02.017. Epub 2021 Mar 5. [Article]
- FDA Approved Drug Products: SIRTURO® (bedaquiline) tablets, for oral use (October 2023) [Link]
- FDA Approved Drug Products: SIRTURO (bedaquiline) tablets, for oral use [Link]
- External Links
- KEGG Drug
- D09872
- KEGG Compound
- C14122
- PubChem Compound
- 5388906
- PubChem Substance
- 175427143
- ChemSpider
- 4534966
- BindingDB
- 50063995
- 1364504
- ChEBI
- 72292
- ChEMBL
- CHEMBL376488
- ZINC
- ZINC000004655029
- PDBe Ligand
- BQ1
- RxList
- RxList Drug Page
- Wikipedia
- Bedaquiline
- PDB Entries
- 4v1f / 7jg8 / 7jg9 / 7jga / 7jgc / 7njv
- FDA label
- Download (505 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Not Yet Recruiting Treatment Nontuberculous Mycobacterial Lung Disease 1 4 Recruiting Treatment Multidrug Resistant Tuberculosis 1 3 Active Not Recruiting Treatment Bacterial Infections / Gram Positive Bacterial Infections / Multidrug Resistant Tuberculosis / Mycobacterial Infections / Pulmonary Tuberculoses / Tuberculosis (TB) 1 3 Active Not Recruiting Treatment Extensively Drug Resistant Tuberculosis / Multidrug Resistant Tuberculosis / Pre-XDR-TB / Rifampicin Resistant Tuberculosis / Tuberculosis (TB) 1 3 Active Not Recruiting Treatment Non-responsive Multidrug-Resistant Pulmonary TB / Pre-Extensively Drug-Resistant Pulmonary TB / Treatment Intolerant Multidrug-Resistant Pulmonary TB 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet Oral 100 mg/1 Tablet Oral 100.000 mg Tablet Oral 20 mg/1 Tablet Oral 20 MG Tablet Oral 100 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7498343 No 2009-03-03 2024-10-02 US US8546428 No 2013-10-01 2029-03-19 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Insoluble FDA label - Predicted Properties
Property Value Source Water Solubility 0.000193 mg/mL ALOGPS logP 6.37 ALOGPS logP 7.13 Chemaxon logS -6.5 ALOGPS pKa (Strongest Acidic) 13.61 Chemaxon pKa (Strongest Basic) 8.91 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 45.59 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 154.02 m3·mol-1 Chemaxon Polarizability 57.29 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9811 Blood Brain Barrier + 0.8854 Caco-2 permeable + 0.6526 P-glycoprotein substrate Substrate 0.7553 P-glycoprotein inhibitor I Inhibitor 0.7137 P-glycoprotein inhibitor II Inhibitor 0.5998 Renal organic cation transporter Non-inhibitor 0.554 CYP450 2C9 substrate Non-substrate 0.814 CYP450 2D6 substrate Non-substrate 0.5081 CYP450 3A4 substrate Substrate 0.8225 CYP450 1A2 substrate Inhibitor 0.6983 CYP450 2C9 inhibitor Non-inhibitor 0.6497 CYP450 2D6 inhibitor Inhibitor 0.5348 CYP450 2C19 inhibitor Non-inhibitor 0.5469 CYP450 3A4 inhibitor Non-inhibitor 0.6535 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5292 Ames test Non AMES toxic 0.6998 Carcinogenicity Non-carcinogens 0.9055 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.7887 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9607 hERG inhibition (predictor II) Inhibitor 0.6476
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 209.74884 predictedDeepCCS 1.0 (2019) [M+H]+ 211.96225 predictedDeepCCS 1.0 (2019) [M+Na]+ 217.79915 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Mycobacterium tuberculosis
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- F(1)F(0) ATP synthase produces ATP from ADP in the presence of a proton or sodium gradient. F-type ATPases consist of two structural domains, F(1) containing the extramembraneous catalytic core and F(0) containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation.
- Specific Function
- Lipid binding
- Gene Name
- atpE
- Uniprot ID
- P9WPS1
- Uniprot Name
- ATP synthase subunit c
- Molecular Weight
- 8055.41 Da
References
- Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, Ristic Z, Lill H, Dorange I, Guillemont J, Bald D, Andries K: Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 2007 Jun;3(6):323-4. Epub 2007 May 13. [Article]
- FDA Approved Drug Products: SIRTURO® (bedaquiline) tablets, for oral use (October 2023) [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: SIRTURO® (bedaquiline) tablets, for oral use (October 2023) [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Toxic substance binding
- Specific Function
- Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Serum albumin
- Molecular Weight
- 69365.94 Da
References
- van Heeswijk RP, Dannemann B, Hoetelmans RM: Bedaquiline: a review of human pharmacokinetics and drug-drug interactions. J Antimicrob Chemother. 2014 Sep;69(9):2310-8. doi: 10.1093/jac/dku171. Epub 2014 May 23. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Not Available
- Specific Function
- Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
- Gene Name
- ORM1
- Uniprot ID
- P02763
- Uniprot Name
- Alpha-1-acid glycoprotein 1
- Molecular Weight
- 23511.38 Da
References
- van Heeswijk RP, Dannemann B, Hoetelmans RM: Bedaquiline: a review of human pharmacokinetics and drug-drug interactions. J Antimicrob Chemother. 2014 Sep;69(9):2310-8. doi: 10.1093/jac/dku171. Epub 2014 May 23. [Article]
Drug created at June 10, 2013 21:32 / Updated at January 02, 2024 23:48