Bedaquiline

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
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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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatPulmonary multi-drug resistant tuberculosis (mdr-tb)•••••••••••••••••• ••••••••••••• •••••• •• •• ••••• •• ••••••••
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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.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

TargetActionsOrganism
AATP synthase subunit c
inhibitor
Mycobacterium 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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Toxicity

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
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.
DrugInteraction
AbametapirThe serum concentration of Bedaquiline can be increased when it is combined with Abametapir.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Bedaquiline.
AcenocoumarolThe risk or severity of bleeding can be increased when Bedaquiline is combined with Acenocoumarol.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Bedaquiline.
AdagrasibThe 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

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Product Ingredients
IngredientUNIICASInChI Key
Bedaquiline fumarateP04QX2C1A5845533-86-0ZLVSPMRFRHMMOY-WWCCMVHESA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SirturoTablet100 mgOralJanssen Cilag International Nv2016-09-08Not applicableEU flag
SirturoTablet20 mgOralJanssen Cilag International Nv2022-05-04Not applicableEU flag
SirturoTablet100 mg/1OralJanssen Products, LP2012-12-28Not applicableUS flag
SirturoTablet100 mgOralJanssen Cilag International Nv2016-09-08Not applicableEU flag
SirturoTablet20 mg/1OralJanssen Products, LP2020-05-27Not applicableUS flag

Categories

ATC Codes
J04AK05 — Bedaquiline
Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. FDA Approved Drug Products: SIRTURO® (bedaquiline) tablets, for oral use (October 2023) [Link]
  7. FDA Approved Drug Products: SIRTURO (bedaquiline) tablets, for oral use [Link]
KEGG Drug
D09872
KEGG Compound
C14122
PubChem Compound
5388906
PubChem Substance
175427143
ChemSpider
4534966
BindingDB
50063995
RxNav
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
FormRouteStrength
TabletOral
TabletOral100 mg/1
TabletOral100.000 mg
TabletOral20 mg/1
TabletOral20 MG
TabletOral100 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7498343No2009-03-032024-10-02US flag
US8546428No2013-10-012029-03-19US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsoluble FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.000193 mg/mLALOGPS
logP6.37ALOGPS
logP7.13Chemaxon
logS-6.5ALOGPS
pKa (Strongest Acidic)13.61Chemaxon
pKa (Strongest Basic)8.91Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area45.59 Å2Chemaxon
Rotatable Bond Count8Chemaxon
Refractivity154.02 m3·mol-1Chemaxon
Polarizability57.29 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9811
Blood Brain Barrier+0.8854
Caco-2 permeable+0.6526
P-glycoprotein substrateSubstrate0.7553
P-glycoprotein inhibitor IInhibitor0.7137
P-glycoprotein inhibitor IIInhibitor0.5998
Renal organic cation transporterNon-inhibitor0.554
CYP450 2C9 substrateNon-substrate0.814
CYP450 2D6 substrateNon-substrate0.5081
CYP450 3A4 substrateSubstrate0.8225
CYP450 1A2 substrateInhibitor0.6983
CYP450 2C9 inhibitorNon-inhibitor0.6497
CYP450 2D6 inhibitorInhibitor0.5348
CYP450 2C19 inhibitorNon-inhibitor0.5469
CYP450 3A4 inhibitorNon-inhibitor0.6535
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5292
Ames testNon AMES toxic0.6998
CarcinogenicityNon-carcinogens0.9055
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7887 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9607
hERG inhibition (predictor II)Inhibitor0.6476
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0010090000-091762cd817abab38abb
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-1022390000-7b54f5930a9c4ad0eb7f
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-2020490000-c2a40c89af4d5b6d4561
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0fb9-9010060000-849971650d1d58307b92
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-052f-9221310000-70c6b1ed3bb61b7e826a
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9001000000-a16e549513421cff4c1a
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-209.74884
predicted
DeepCCS 1.0 (2019)
[M+H]+211.96225
predicted
DeepCCS 1.0 (2019)
[M+Na]+217.79915
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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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
  1. 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]
  2. 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
  1. 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
  1. 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
  1. 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