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. Chemically it is a diarylquinoline. FDA approved on December 28, 2012.
- 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 adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB).
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- 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 to 6-fold lower) compared to the parent compound. M2 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. Furthermore, bacteria that have smaller ATP stores (usually in dormant, nonreplicating bacilli) are more susceptible to bedaquiline.
- Mechanism of action
Bedaquiline is a diarylquinoline antimycobacterial drug that inhibits the proton pump of mycobacterial ATP (adenosine 5'-triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis. Bacterial death occurs as a result of bedaquiline.
Target Actions Organism AATP synthase subunit c inhibitorMycobacterium tuberculosis - Absorption
Tmax, oral dose = 5 hours; Food increases the oral bioavailability. AUC increases proportionally up to the highest dose studied in healthy volunteers. When 400 mg of bedaquiline is administered once daily for a week, the peak plasma concentration (Cmax) is 5.5 μg/ml and an AUC of 64.75 μgh/ml.
- Volume of distribution
Vd, central compartment = 164 L
- Protein binding
>99.9 bound to plasma proteins.
- Metabolism
Bedaquiline is hepatically metabolized. The main enzyme involved is CYP3A4 which metabolizes bedaquiline into the N-monodesmethyl metabolite (M2). This metabolite is 4 to 6-times less active in terms of antimycobacterial potency.
- Route of elimination
Bedaquiline is primarily elimination in the 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.
- Half-life
Terminal elimination half-life, bedaquiline and M2 = 5.5 months. This long half-life suggests slow release of bedaquiline and M2 from peripheral tissues.
- Clearance
Not Available
- Adverse Effects
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The most common adverse reactions reported in ≥10% of patients treated with bedaquiline are nausea, arthralgia, and headache.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- 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. 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. Adenosine The risk or severity of QTc prolongation can be increased when Adenosine is combined with Bedaquiline. Ajmaline The risk or severity of QTc prolongation can be increased when Ajmaline is combined with Bedaquiline. Alfuzosin The risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Bedaquiline. Alimemazine The risk or severity of QTc prolongation can be increased when Alimemazine is combined with Bedaquiline. Amantadine The risk or severity of QTc prolongation can be increased when Amantadine is combined with Bedaquiline. Amifampridine The risk or severity of QTc prolongation can be increased when Bedaquiline is combined with Amifampridine. Amiodarone The metabolism of Bedaquiline can be decreased when combined with Amiodarone. 
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- 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
- Mycobacterium tuberculosis
- 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]
- 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
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet Oral 100 mg/1 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
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
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- 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]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
Drug created at June 10, 2013 21:32 / Updated at January 03, 2023 04:23