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|Year : 2014 | Volume
| Issue : 3 | Page : 300-302
Bedaquiline: A novel antitubercular drug for multidrug-resistant tuberculosis
H Nagabushan, HS Roopadevi
Department of Pharmacology, Mandya Institute of Medical Sciences, Mandya, Karnataka, India
|Date of Submission||09-Apr-2013|
|Date of Decision||20-Apr-2013|
|Date of Acceptance||02-Jun-2014|
|Date of Web Publication||14-Aug-2014|
Dr. H Nagabushan
Department of Pharmacology, Mandya Institute of Medical Sciences, Mandya, Karnataka
Source of Support: None, Conflict of Interest: None
Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are emerging global health threats. Bedaquiline is a new antituberculous drug belonging to the diarylquinoline class that efficiently inhibits the adenosine triphosphate synthase enzyme of Mycobacterium tuberculosis. It is a bactericidal and long-acting drug. It inhibits both dormant as well as replicating bacterial sub-populations and thus shortens the duration of TB treatment. This drug has been approved by the Food and Drug Administration in December 2012 for the management of multidrug resistant-TB. The drug marks the introduction of a new addition to the TB armamentarium after four decades.
Keywords: Adenosine triphosphate synthase enzyme, bedaquiline, multidrug-resistant tuberculosis, Mycobacterium tuberculosis
|How to cite this article:|
Nagabushan H, Roopadevi H S. Bedaquiline: A novel antitubercular drug for multidrug-resistant tuberculosis. J Postgrad Med 2014;60:300-2
| :: Introduction|| |
Tuberculosis (TB) causes considerable morbidity among millions of people each year worldwide and ranks as the second leading cause of death from an infectious disease, after the human immunodeficiency virus (HIV). As per current estimates, there were about 9 million new cases in 2011 and 1.4 million TB deaths (990,000 among HIV-negative people and 430,000 HIV-associated TB deaths). 
Bedaquiline is a new antituberculous drug belonging to the diarylquinoline class that efficiently inhibits the adenosine triphosphate synthase enzyme of Mycobacterium tuberculosis. Bedaquiline offers a new mechanism of anti-TB action by specifically inhibiting mycobacterial adenosine triphosphate (ATP) synthase. Diarylquinolines belong to the quinoline class of compounds, possessing a quinolinic central heterocyclic nucleus and side chains of tertiary alcohol and tertiary amine groups that are responsible for their antimycobacterial action [Figure 1]. ,
Mechanism of action
- It is a bactericidal drug that inhibits the proton pump of mycobacterial ATP synthase, a critical enzyme in the synthesis of ATP for Mycobacterium tuberculosis. ,
- It binds to the oligomeric and proteolipic subunit c of mycobacterial ATP synthase, leading to the inhibition of ATP synthesis, which subsequently results in bacterial death. 
- Targets the atpE gene encoding the subunit c of the ATP synthase of Mycobacterium tuberculosis. 
Mechanism of resistance
- The presence of mutations at position 63 (proline substituting alanine) or at position 66 (methionine substituting leucine) of the atpE gene disrupts the capacity of bedaquiline to bind to one of the subunits of ATP synthase enzyme. 
- This confers either natural (as in Mycobacterium xenopi and other non-tuberculous mycobacteria-NTM species) or acquired (as in Mycobacterium tuberculosis mutants) resistance. 
Bedaquiline susceptible: Mycobacterium tuberculosis, Mycobacterium avium complex.
Bedaquiline resistant: Mycobacterium novocastrense, Mycobacterium xenopi, Mycobacterium shimoidei.  It inhibits both dormant as well as replicating bacterial sub-populations and thus shortens the duration of TB treatment.  It has a broad antimycobacterial activity and hence can be used in the treatment of non-tuberculous mycobacteria that are typically difficult to manage with standard medical treatment, but is only bacteriostatic against Mycobacterium avium. , Oral once-daily administration of bedaquiline has bactericidal activity at a dose of 400 mg when administered as monotherapy for 7 days in patients with pulmonary TB. Compared with Isoniazid (INH) and Rifampin, the bactericidal activity of 400 mg of bedaquiline starts later but is of similar magnitude on Days 4-7. 
Bedaquiline is rapidly absorbed orally and metabolized slowly. N-Desmethyl metabolite is the major circulating metabolite. The exposure to metabolite is four- to five-fold lower than that of the parent drug.  After oral administration, the maximum plasma concentrations (Cmax) of Bedaquiline are typically achieved at approximately 5 h post-dose.
Plasma protein binding is greater than 99.9%. and the volume of distribution is -164 L.
Oxidative metabolism via cytochrome P450 isoenzyme CYP3A4.  Elimination is slow, with half-lives of 50-60 h.  The majority of the drug gets eliminated in the feces.
- Bedaquiline was very effective in guinea pigs, with complete eradication of Mycobacterium tuberculosis from both primary and secondary lesions in the lung granulomas when given for 6 weeks. 
- In mice, the bactericidal activity was accelerated when bedaquiline was substituted to the World Health Organization's (WHO) first-line TB treatment regimen (Rifampin, INH and Pyrazinamide). Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. 
- Combinations including bedaquiline but not pyrazinamide (e.g., bedaquiline-INH-Rifampicin and bedaquiline-Moxifloxacin-Rifampicin) were less active than bedaquiline-pyrazinamide-containing regimens administered either alone or with the addition of INH, Rifampicin or Moxifloxacin. These results revealed a synergistic interaction between bedaquiline and pyrazinamide. 
- Pyrazinamide is an indirect inhibitor of ATP synthase, acts by disrupting the membrane potential, which is required by the enzyme to generate ATP,  and thus add to the specific ATP-synthase inhibition of bedaquiline. Bedaquiline has shown enhancement in the antibacterial activity of second-line drug combinations in the murine model of drug-sensitive TB. 
- The triple-drug combination of bedaquiline-Rifapentine-pyrazinamide displayed unprecedented bactericidal activity in mice, and raised the possibility of developing a new, fully intermittent short-course regimen for the therapy of TB. 
- Addition of bedaquiline to the standard Rifampicin, Isoniazid, Pyrazinamide RHZ regimen was effective, despite the drug-drug interactions between Rifampicin and bedaquiline, where Rifampicin reduces the bioavailability of bedaquiline by 50%. 
- Bedaquiline can be substituted for INH or can be supplemented to the standard anti-TB regimen to reduce the TB treatment duration to 4 months. 
Bedaquiline was also effective in the treatment of leprosy, both in low and intermittent dosing. 
- A phase IIa, open-label, randomized clinical trial designed to evaluate the pharmacokinetics, safety, tolerability and extended early bactericidal activities of three different daily oral doses of bedaquiline (25, 100 or 400 mg) administered as monotherapy over a treatment period of 7 days in treatment-naive patients with sputum smear-positive pulmonary TB showed that oral once-daily administration of bedaquiline has bactericidal activity at a dose of 400 mg. Compared with INH and Rifampin, the bactericidal activity of 400 mg of bedaquiline starts later, but is of similar magnitude on Days 4-7. 
- In the first stage of a two-stage, phase 2, randomized, controlled trial, ATP synthase was validated as a viable target for the treatment of TB.  The findings also confirmed the earlier results obtained with bedaquiline in the murine model of TB  and demonstrated that it was effective in the treatment of patients with multidrug-resistant tuberculosis (MDR-TB). 
- It was approved by the Food and Drug Administration in December 2012 as a part of combination therapy in adults (≥18 years) with pulmonary MDR-TB when an effective treatment regimen cannot otherwise be provided. 
Dosage and administration
• It should only be used in combination with at least three other drugs to which the patient's MDR-TB isolate has been shown to be susceptible in vitro.
- Weeks 1-2: 400 mg (four tablets of 100 mg) once daily with food.
- Weeks 3-24: 200 mg (two tablets of 100 mg) three-times per week with food (with at least 48 h between doses) for a total dose of 600 mg/week.
Dosage form and strength
100 mg tablet.
Hypersensitivity reaction to the drug.
- Cutaneous - rash, pruritus, acne.
- Central nervous system - dizziness, unilateral/bilateral deafness, headache. ,
- Gastrointestinal tract - diarrhea, nausea, vomiting, pain abdomen.
- Musculoskeletal and connective tissue - arthralgia, extremity pain, back pain, hyperuricemia.
- Respiratory - hemoptysis, pleuritic pain, pharyngolaryngeal pain. 
- Cardiovascular - prolongation of QT-interval. 
- Liver - elevated transaminases. 
- CYP3A4 inducers/inhibitors Rifampin (strong CYP3A4 inducer) - Rifampicin reduces the AUC of bedaquiline by 50% in humans and hence the expected efficacy of Bedaquiline in humans is less than that observed in mice.  Ketoconazole (strong CYP3A4 inhibitor) - Increases the exposure (AUC) to bedaquiline by 22%. 
- Other antimicrobial medications- Pyrazinamide enhances the antibacterial activity of bedaquiline by indirectly inhibiting ATP synthase. 
- Antiretroviral medications- Combination of Lopinavir and Ritonavir - increases the bioavailability of bedaquiline by 22%.
- QT interval-prolonging drugs-Synergistic QT prolongation was observed when bedaquiline was co-administered with other drugs that prolong the QT interval. 
Use in specific populations
- Pregnancy - Category B.
- Nursing mothers - not known whether bedaquiline or its metabolites are excreted in human milk, but rat studies have shown that the drug is concentrated in breast milk.
- Pediatric use - safety and efficacy in children and adolescents less than 18 years of age has not been established. 
| :: Conclusion|| |
Bedaquiline, a new class of drug for TB, has come to the market after more than three decades. Bedaquiline is a diarylquinolone compound with a novel mechanism of action and potent activity against drug-sensitive and drug-resistant TB. It has a bactericidal and sterilizing activity against Mycobacterium tuberculosis and other mycobacterial species, but little activity against other bacteria. The drug appears to be safe and well tolerated.
| :: References|| |
|1.||The World Health Organization (WHO) Global Tuberculosis Report 2012. Available from:http://www.who.int/tb/publications/global_report/gtbr12_main.pdf. [Last accessed on 2013 Apr 04]. |
|2.||Matteelli A, Carvalho AC, Dooley KE, Kritski A. TMC207: The first compound of a new class of potent anti-tuberculosis drugs. Future Microbiol 2010;5:849-58. |
|3.||Gaurrand S, Desjardins S, Meyer C, Bonnet P, Argoullon JM, Oulyadi H, et al. Conformational analysis of r207910, a new drug candidate for the treatment of tuberculosis, by a combined NMR and molecular modeling approach. ChemBiol Drug Des 2006;68:77-84. |
|4.||Petrella S, Cambau E, Chauffour A, Andries K, Jarlier V, Sougakoff W. Genetic basis for natural and acquired resistance to the diarylquinoline R207910 in mycobacteria. Antimicrob Agents Chemother 2006;50:2853-6. |
|5.||Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother 2007;51:4202-4. |
|6.||Koul A, Vranckx L, Dendouga N, Balemans W, Van denWyngaert I, Vergauwen K, et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J BiolChem 2008;283:25273-80. |
|7.||Lounis N, Gevers T, Van den Berg J, Vranckx L, Andries K. ATP synthase inhibition of Mycobacterium aviumis not bactericidal.Antimicrob Agents Chemother 2009;53:4927-9. |
|8.||Rustomjee R, Diacon AH, Allen J, Venter A,Reddy C,Patientia RF, et al. Early bactericidal activity and pharmacokinetics of the dairylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob Agents Chemother 2008;52:2831-5. |
|9.||Rouan MC, Lounis N, Gevers T, Dillen L, Gilissen R, Raoof A, et al. Pharmacokinetics and pharmacodynamics of TMC207 and its N-desmethyl metabolite in a murine model of tuberculosis. Antimicrob Agents Chemother 2012;56:1444-51. |
|10.||Lenaerts AJ, Hoff D, Aly S, Ehlers S, Andries K, Cantarero L, et al. Location of persisting mycobacteria in a Guinea pig model of tuberculosis revealed by r207910. Antimicrob Agents Chemother 2007;51:3338-45. |
|11.||Andries K, Verhasselt P, Guillemont J,Göhlmann HW, Neefs JM, Winkler H, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307:223-7. |
|12.||Ibrahim M, Andries K, Lounis N,Chauffour A, Truffot-Pernot C, Jarlier V, et al. Synergistic activity of R207910 combined with pyrazinamide against murine tuberculosis. Antimicrob Agents Chemother 2007;51:1011-5. |
|13.||Zhang Y, Wade MM, Scorpio A, Zhang H, Sun Z. Mode of action of pyrazinamide: Disruption of Mycobacterium tuberculosismembrane transport and energetics by pyrazinoic acid. J Antimicrob Chemother 2003;52:790-5. |
|14.||Lounis N, Veziris N, Chauffour A, Truffot-Pernot C, Andries K, Jarlier V. Combinations of R207910 with drugs used to treat multidrug-resistant tuberculosis have the potential to shorten treatment duration. Antimicrob Agents Chemother 2006;50:3543-7. |
|15.||Veziris N, Ibrahim M, Lounis N,Chauffour A, Truffot-Pernot C, Andries K, et al. A once-weekly R207910-containing regimen exceeds activity of the standard daily regimen in murine tuberculosis. Am J Respir Crit Care Med 2009;179:75-9. |
|16.||Lounis N, Gevers T, Van Den Berg J, Andries K. Impact of the interaction of R207910 with rifampin on the treatment of tuberculosis studied in the mouse model. Antimicrob Agents Chemother 2008;52:3568-72. |
|17.||Ibrahim M, Truffot-Pernot C, Andries K, Jarlier V, Veziris N. Sterilizing activity of R207910 (TMC207)-containing regimens in the murine model of tuberculosis. Am J Respir Crit Care Med 2009;180:553-7. |
|18.||Gelber R, Andries K, Paredes RM, Andaya CE, Burgos J. The diarylquinoline R207910 is bactericidal against Mycobacterium lepraein mice at low dose and administered intermittently. Antimicrob Agents Chemother 2009;53:3989-91. |
|19.||Diacon AH, Pym A, Grobusch M,Patientia R, Rustomjee R, Page-Shipp L, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 2009;360:2397-405. |
|20.||Medication Guideof Bedaquiline Tablet. Available from:http://www.fda.gov/downloads/Drugs/DrugSafety/UCM333729.pdf. [Last accessed on 2013 Apr 05]. |
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