International Journal of Drug Development and Research

References

1. 1) Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163: 1009-21.
2. 2) TB India 2012. Revised National TB Control Programme. Annual status report 2012. Govt. of India. Tuberculosis epidemiology-India. Page 7.
3. 3) "Global Tuberculosis Control 2012, WHO, Geneva, 2012 https://www.who.int/tb/publications/global_report/en
4. 4) DakshinaBisht. Can Newer Diagnostic Microbiological Assays Guide Early Tuberculosis Management? Indian J Tuberc 2011; 58:51-53.
5.  5) Sinha K. "Finally, tuberculosis declared a notifiable disease", The Times of India, May 9, 2012. https://articles.timesofindia.indiatimes.com/2012-05- 09/india/31640562_1_mdr-tb-tb-cases-tb-diagnosis.
6. 6) Rajendra Prasad. Multidrug And Extensively Drug- Resistant Tb (M / Xdr-Tb): Problems and Solutions. Indian J Tuberc 2010; 57: 180-191.
7. 7) Global Tuberculosis Report 2012. Chapter 2, The Burden of disease caused by TB, WHO, Geneva. Page 20.
8. 8) Holtz TH, Cegielski JP. Origin of the term XDR-TB. Eur. Respir. J. 2007; 30: 396.
9.  9) Migliori GB, Loddenkemper R, Blasi F et al. 125 years afterRobert Koch’s discovery of the tubercle bacillus: the newXDR-TB threat. Is ‘science’ enough to tackle the epidemic? Eur. Respir. J. 2007; 29: 423–7.
10. 10) Katherine Rowland (13 January 2012). "Totally drug- resistant TB emerges in India". Nature. https://www.nature.com/news/totally-drug-resistant- tb-emerges-in-india-1.9797
11. 11) Velayati AA, Masjedi MR, Farnia P, et al. Emergence of new forms of totally drug resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug resistant strains in Iran. Chest 2009; 136:420–5.
12. 12) Nachega j b, chaisson r e. Tuberculosis drug resistance: a global threat. Clin infect dis 2003; 36 (suppl 1): s24–s30.
13. 13) Chen-yuan Chiang, Rosella Centis and Giovanni Battista Migliori. Drug-resistant tuberculosis: past, present, future. Respirology(2010) 15, 413–432.
14. 14) "FDA Approves 1st New Tuberculosis Drug in 40 Years". Yahoo news. Retrieved 31 December 2012. https://news.yahoo.com/fda-approves-1st-tuberculosis- drug-40-years-152508824--finance.html.
15. 15) Matthew Perrone."F.D.A. Approves New Tuberculosis Drug". New York Times. Retrieved 31 December 2012. www.boston.com/.../fda-approves-new-tuberculosis- drug.../story.html.
16. 16) deJonge MR, Koymans LH, Guillemont JE, Koul A, Andries K (June 2007). "A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910". Proteins67 (4): 971–80.
17. 17) "J&J&J Sirturo Tuberculosis Drug Gets Fast-Track Clearance". Wall Street Journal. Retrieved 2013-01- 01.)
18. 18) https://www.fda.gov/NewsEvents/Newsroom/PressAn nouncements/ucm333695.htm 19) Bedaquiline - Compound Summary. https://pubchem.ncbi.nlm.nih.gov/summary/summary .cgi?cid=5388906.
19. 20) en.wikipedia.org/wiki/Bedaquiline
20. 21) Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307:223-7.
21.  22) Koul A, Dendouga N, Vergauwen K, et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat ChemBiol 2007;3:323-4.
22. 23) 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.
23. 24) Koul A, Vranckx L, Dendouga N, et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J BiolChem 2008;283: 25273-80.
24. 25) Rouan MC, Lounis N, Gevers T, et al. Pharmacokinetics and pharmacodynamics of TMC207 and its N-desmethyl metabolite in a murine model of tuberculosis. Antimicrob Agents Chemother 2012; 56: 1444–1451.
25. 26) Highlights of prescribing information [Internet]. Initial U.S. Approval-2012. Reference ID: 3237647 available from: www.accessdata.fda.gov/drugsatfda_docs/label/.../20 4384s000lbl.pdf.(accessed on 9th feb2013).
26. 27) Ibrahim M, Andries K, Lounis N, et al. with pyrazinamide against murine tuberculosis Antimicrob Agents Chemother2007;51:1011-5.
27. 28) Lounis N, Veziris14. 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.
28. 29) Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, McNeeley DF. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405.
29. 30) Diacon AH, Donald PR, Pym A, Grobusch M, Patientia RF, Mahanyele R, Bantubani N, Narasimooloo R, De Marez T, van Heeswijk R, Lounis N, Meyvisch P, Andries K, McNeeley DF. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother. 2012 Jun;56(6):3271-6.
30. 31) A Study to Evaluate the Efficacy and Safety of TMC207 in Patients with Pulmonary Infection with Multi-drug Resistant Mycobacterium Tuberculosis. https://clinicaltrials.gov/ct2/show/NCT01600963acces sed on February 11, 2013.
31. 32) https://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/Anti- InfectiveDrugsAdvisoryCommittee/UCM329260.pdf

Key words

Bedaquiline, Tuberculosis, MDR-TB, XDR-TB.

Introduction

Tuberculosis (TB) remains a major global health problem and stands a leading cause of death due to infectious disease, second only to human immunodeficiency virus and acquired immunodeficiency syndrome.1For several decades in the developing countries, eradication of tuberculosis remains to be a primary health challenge despite regular TB control programs adopted by governments. According to WHO-TB statistics for 2011, India has the highest TB burden country with an estimated incidence of 2.2 million cases out of a global incidence of 8.7 million cases and 1.4 million TB deaths.2,3 The TB prevalence in India for 2011 is estimated to be 3.1 million cases.3In India,TB bares the highest mortality rate in humans among the infectious diseases, about 3 million deaths annually, 5 deaths every minute.4Therefore, to curtail the existing problem in India, a notification was sent to all states, declaring TB to be a notifiable disease, which means all health care professionals treating a TB patient had to report immediately every case of TB to the government.5

Short-course regimens of first-line drugs that can cure around 90% of cases have been available since the 1980s.3Inadequate TB treatment or harboring drug resistant tubercle bacilli can lead to the development of drug resistant TB. TB control is challenged by MDR-TB and XDR-TB. MDR-TB is defined as resistance to isoniazid (INH) and rifampicin (RMP) two of the most effective anti-TB drugs, with or without resistance to other drugs.6Globally in 2011, there were an estimated 630,000 cases of MDR-TB among the world’s 12 million prevalent cases of TB.7XDR-TB is defined as resistance to INH and RMP plus any fluoroquinolone and at least one of the injectable agents: kanamycin [KM], amikacin [AMK] or capreomycin [CPM]).8, 9Totally drug resistant TB(XXDR-TB or TDR-TB) is defined as resistant to a wider range of drugs has also now been detected. TDR-TB is resistant to all the first and second line TB drugs and it is extremely difficult to treat.10, 11

Novel TB drugs are obligatoryto tackle the major problem of prevention and treatment of drug resistance. The expansion of newer agents is an urgent priority for the restraint of MDR-TB and XDR-TB and also need for better and rapid diagnostic assays for early detection of TB.12, 13Several new molecules and early detection techniques are being researched in the management of TB; BEDAQUILINE is the first new FDA approved drug in 40 years to fight against MDR-TB.14, 15

Drug review:

Adiarylquinoline anti-tuberculosis drug, Bedaquiline (also known as Sirturo, TMC207 or R207910)was discovered by a team led by the BelgianKoenAndries at Janssen Pharmaceutica.16It is manufactured by Johnson & Johnson (J&J), who sought accelerated approval of the drug for treatment of multi-drug-resistant tuberculosis.17On 28thDecember 2012, the U.S. Food and Drug Administration approved bedaquiline, as part of combination therapy to treat adults with multi-drug resistant tuberculosis (MDR-TB) when other alternatives are not available and also granted Sirturo fast track designation, priority review and orphanproduct designation.18 The drug demonstrated the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no satisfactory alternative therapy exists. 18

Chemical structure: 19, 20

IUPAC Name: (1R, 2S)-1-(6-bromo-2- methoxyquinolin-3-yl)-4-(dimethylamino)-2- naphthalen-1-yl-1-phenylbutan-2-ol. Molecular Formula: C32H31BrN2O2

Mechanism of action:

TMC207 a diarylquinoline compound that offers a new mechanism of antituberculosis action by specifically targeting mycobacterial proton pump of adenosine triphosphate (ATP) synthase, leading to inadequate synthesis of ATP (reduced generation of energy in Mycobacterium tuberculosis).21, 22Its MIC for M. tuberculosis is 0.06 μg/ml and it has no cross resistance with existing anti-tuberculosis antibiotics. 21Bedaquiline is active against most isolates of Mycobacterium tuberculosis. In vitro, TMC207 potently inhibits drug-sensitive and drug-resistant M. tuberculosis isolates 21, 23and is also bactericidal against dormant (non-replicating) tubercle bacilli.24TMC207 has shown concentrationdependent anti-bacterial activity. 25

Pharmacokinetics:26

Bedaquiline is well absorbed orally and post dose maximum plasma concentration (Cmax) is 5 hours. Food increases its bioavailability. The plasma protein binding of bedaquiline is > 99.9%. The volume of distribution in the central compartment is estimated to be approximately 164 L. Cytochrome P4503A4 metabolizes TMC207 into its major Nmonodesmethyl metabolite, which is about five times less active than the parent compound. Both compounds are eliminated with long terminal halflives of 50–60 hrs in mice, suggesting extensive tissue binding.25Based on preclinical studies, bedaquiline is eliminated mainly 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.

Efficacy studies:

Preclinical studies: Bedaquiline exhibited potential antimycobacterial activity and also accelerated clearance of bacilli, as similar tothe combination of isoniazid, rifampin, and pyrazinamide in the murine model of tuberculosis.21TMC207 showed synergistic interaction with pyrazinamide. 27 Similarly, TMC207 enhances the antibacterial activity of second-line drug combinations in the murine model of drugsensitive tuberculosis.28

Clinical studies:

The demonstration of antimycobacterial potential of bedaquiline in preclinical modelspaved way for further efficacy studies in humans.The drug has been approved on the basis of the results of two phase II trials. The study was randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability and efficacy of bedaquiline when it is added to a background regimen (BR) in newly diagnosed patients with MDR pulmonary TB was conducted in two stages. Both studies were designed to measure the time to conversion to a negative sputum culture.

In the first trial29, newly diagnosed, smear positive MDR-TB (pulmonary) patients were randomly assigned to be treated with bedaquiline or placebo in combination with a standard five-drug regimen, second-line anti-tuberculosis regimen for 8 weeks. This study revealed, the addition of TMC207 (48%) to the standard drug regimen for MDR-TB resulted in quicker conversion to a negative sputum culture compared to placebo group (9%).The median rates of smear negative for acid-fast bacilli at week 4 were 77% and 57% for the TMC207 and placebo group and at week 8 were 84% and 68% for the TMC207 and placebo group respectively. Also TMC207had an acceptable side-effect profile. 29

In the second trial30, all patients received either bedaquiline or placebo for 24 weeks in addition to other anti-TB drugs. The median time of sputum culture conversion were 78 days for TMC207, compared with 129 days in patients treated with placebo.Those who received TMC207 were at lower risk of acquisition of additional drug resistance over the whole duration of follow-up. The side effects incidence was similar in the patients who received bedaquiline (82.6%) compared to those who had received placebo (79.2%). The majority of the adverse events recorded here were of mild or moderate intensity. A phase 3 trial of bedaquiline, TMC207- C210, is due to start in March 2013. It will be a double blind study of 600 patients with sputum smear positive MDR-TB, which will compare TB treatment with bedaquiline and a background regimen, with placebo and a background regimen.31

Safety and tolerability:26

The most common adverse reactions reported were nausea, arthralgia, and headache. Other adverse events reported were hemoptysis and chest pain in R10% of patients treated with bedaquiline, with a higher frequency than the placebo treatment group.26,29 No clinically relevant heart rate changes or electrocardiographic QRS or PR interval were observed during the study. In both the treatment groups, mean increase in the corrected QT interval was observed but was more pronounced in the TMC207 group (p> 0.05). No dosage adjustment is required in patients with mild to moderate renal or hepatic impairment. Caution in patients with severe renal or hepatic impairment. Alcohol and other hepatotoxic drugs should be avoided.

Dosage and precautions:

The recommended dose of bedaquiline for the treatment of pulmonary MDR-TB in adults is 400mg oncedaily for 2 weeks, followed by 200mg 3 times per week for 22 weeks, with a total duration of 24 weeks, taken with food and in combination with other anti-TB drugs. 26, 32The drug bares a black-box warning for arrhythmias, therefore advised frequent ECG monitoring during the treatment. 18 Withdraw bedaquiline, when total bilirubin elevation > 2xULN or aminotransferase elevations are > 8xULN or aminotransferase elevations persist beyond 2 weeks. 26

CONCLUSION

Adherence to appropriate standards of care and control is imperative and a top priority in order to prevent drug resistance in TB. The occurrence of MDR-TB and XDR-TB is related to poor TB control, due to improper use of second-line anti-TB drugs. The current need of an hour is the rational use of new drugs/regimens for the treatment of TB.Bedaquiline, a new FDA approved drug must be used in combination with other 2nd line anti-tubercular drugs to treat MDR-TB in adults, when other alternatives are not available and it is administered by DOTS. Future prospects include, clinical trials with good study design and large sample size are vital to rationalize the treatment, plus to reduce mortality, morbidity and economic losses, thereby improving TB scenario all over the world. The safety and efficacy of bedaquiline for the treatment of latent TB, drug sensitive TB and extra pulmonary TB has not been established, hence upcoming exploration is necessary in this area.

Tables at a glance

Table 1 Table 2 Table 3 Table 4 Table 5

Figures at a glance

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5

References

1. 1) Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163: 1009-21.
2. 2) TB India 2012. Revised National TB Control Programme. Annual status report 2012. Govt. of India. Tuberculosis epidemiology-India. Page 7.
3. Christian Lienhardt, Global tuberculosis control: lessons learnt and future prospects
4. 4) DakshinaBisht. Can Newer Diagnostic Microbiological Assays Guide Early Tuberculosis Management? Indian J Tuberc 2011; 58:51-53.
5.  5) Sinha K. "Finally, tuberculosis declared a notifiable disease", The Times of India, May 9, 2012. https://articles.timesofindia.indiatimes.com/2012-05- 09/india/31640562_1_mdr-tb-tb-cases-tb-diagnosis.
6. 6) Rajendra Prasad. Multidrug And Extensively Drug- Resistant Tb (M / Xdr-Tb): Problems and Solutions. Indian J Tuberc 2010; 57: 180-191.
7. 7) Global Tuberculosis Report 2012. Chapter 2, The Burden of disease caused by TB, WHO, Geneva. Page 20.
8. 8) Holtz TH, Cegielski JP. Origin of the term XDR-TB. Eur. Respir. J. 2007; 30: 396.
9.  9) Migliori GB, Loddenkemper R, Blasi F et al. 125 years afterRobert Koch’s discovery of the tubercle bacillus: the newXDR-TB threat. Is ‘science’ enough to tackle the epidemic? Eur. Respir. J. 2007; 29: 423–7.
10. 10) Katherine Rowland (13 January 2012). "Totally drug- resistant TB emerges in India". Nature. https://www.nature.com/news/totally-drug-resistant- tb-emerges-in-india-1.9797
11. 11) Velayati AA, Masjedi MR, Farnia P, et al. Emergence of new forms of totally drug resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug resistant strains in Iran. Chest 2009; 136:420–5.
12. 12) Nachega j b, chaisson r e. Tuberculosis drug resistance: a global threat. Clin infect dis 2003; 36 (suppl 1): s24–s30.
13. 13) Chen-yuan Chiang, Rosella Centis and Giovanni Battista Migliori. Drug-resistant tuberculosis: past, present, future. Respirology(2010) 15, 413–432.
14. 14) "FDA Approves 1st New Tuberculosis Drug in 40 Years". Yahoo news. Retrieved 31 December 2012. https://news.yahoo.com/fda-approves-1st-tuberculosis- drug-40-years-152508824--finance.html.
15. 15) Matthew Perrone."F.D.A. Approves New Tuberculosis Drug". New York Times. Retrieved 31 December 2012. www.boston.com/.../fda-approves-new-tuberculosis- drug.../story.html.
16. 16) deJonge MR, Koymans LH, Guillemont JE, Koul A, Andries K (June 2007). "A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910". Proteins67 (4): 971–80.
17. 17) "J&J&J Sirturo Tuberculosis Drug Gets Fast-Track Clearance". Wall Street Journal. Retrieved 2013-01- 01.)
18. 18) https://www.fda.gov/NewsEvents/Newsroom/PressAn nouncements/ucm333695.htm 19) Bedaquiline - Compound Summary. https://pubchem.ncbi.nlm.nih.gov/summary/summary .cgi?cid=5388906.
19. 21) Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307:223-7.
20.  22) Koul A, Dendouga N, Vergauwen K, et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat ChemBiol 2007;3:323-4.
21. 23) 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.
22. 24) Koul A, Vranckx L, Dendouga N, et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J BiolChem 2008;283: 25273-80.
23. 25) Rouan MC, Lounis N, Gevers T, et al. Pharmacokinetics and pharmacodynamics of TMC207 and its N-desmethyl metabolite in a murine model of tuberculosis. Antimicrob Agents Chemother 2012; 56: 1444–1451.
24. 26) Highlights of prescribing information [Internet]. Initial U.S. Approval-2012. Reference ID: 3237647 available from: www.accessdata.fda.gov/drugsatfda_docs/label/.../20 4384s000lbl.pdf.(accessed on 9th feb2013).
25. 27) Ibrahim M, Andries K, Lounis N, et al. with pyrazinamide against murine tuberculosis Antimicrob Agents Chemother2007;51:1011-5.
26. 28) Lounis N, Veziris14. 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.
27. 29) Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, McNeeley DF. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405.
28. 30) Diacon AH, Donald PR, Pym A, Grobusch M, Patientia RF, Mahanyele R, Bantubani N, Narasimooloo R, De Marez T, van Heeswijk R, Lounis N, Meyvisch P, Andries K, McNeeley DF. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother. 2012 Jun;56(6):3271-6.
29. 31) A Study to Evaluate the Efficacy and Safety of TMC207 in Patients with Pulmonary Infection with Multi-drug Resistant Mycobacterium Tuberculosis. https://clinicaltrials.gov/ct2/show/NCT01600963acces sed on February 11, 2013.
30. 32) https://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/Anti- InfectiveDrugsAdvisoryCommittee/UCM329260.pdf