504087
research-article2013
AOPXXX10.1177/1060028013504087Annals of PharmacotherapyChahine et al
Review Article-New Drug Approvals
Bedaquiline: A Novel Diarylquinoline for Multidrug-Resistant Tuberculosis
Annals of Pharmacotherapy 2014, Vol. 48(1) 107–115 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013504087 aop.sagepub.com
Elias B. Chahine, PharmD, BCPS (AQ-ID)1, Lamis R. Karaoui, PharmD, BCPS2, and Hanine Mansour, PharmD, BCPS2
Abstract Objective: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, dosage, and administration of bedaquiline, a novel oral diarylquinoline antimycobacterial agent approved by the Food and Drug Administration for the treatment of adults with pulmonary multidrug-resistant tuberculosis (MDR-TB). Data Sources: A search of PubMed (January 2004-May 2013) and International Pharmaceutical Abstracts (January 2004May 2013) using the search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included proceedings of the Union World Conference on Lung Health. Study Selection and Data Extraction: Preclinical data as well as Phase 1 and 2 studies published in English were evaluated. Data Synthesis: Bedaquiline possesses a unique mechanism of action that disrupts the activity of the mycobacterial adenosine triphosphate synthase. Clinical trials have been conducted evaluating the use of bedaquiline in combination with a background regimen for the treatment of adults with pulmonary MDR-TB. Bedaquiline has an excellent in vitro activity against Mycobacterium tuberculosis, including multidrug resistant M tuberculosis; however, its side effect profile limits its use against MDR-TB when no other effective regimen can be provided. Bedaquiline carries Black Box warnings for increased risk of unexplained mortality and QT prolongation. Bedaquiline is metabolized via the CYP3A4 isoenzyme and thus interacts with rifamycins and several antiretrovirals. Conclusions: In an era of emerging resistance and given the suboptimal efficacy and toxicity of currently available regimens for MDR-TB, bedaquiline represents a great addition to the existing armamentarium of anti-TB agents particularly in areas of the world where the disease is endemic. Keywords bedaquiline, diarylquinoline, antimycobacterial, multi-drug resistant tuberculosis, MDR-TB.
Tuberculosis (TB) remains a major threat, killing millions of people every year around the world. According to the World Health Organization (WHO), in 2011, 8.7 million people were diagnosed with TB, and 1.4 million died from TB-related causes.1 Although the number of TB-infected patients is decreasing, the worldwide burden is still high and the WHO statistics related to the emergence of resistant strains of mycobacteria are alarming.1 According to a WHO estimate, 3.7% of new TB patients has multidrugresistant TB (MDR-TB) defined as TB resistant to both isoniazid and rifampin.2 MDR-TB has emerged as a global public health issue, particularly in Brazil, Russia, India, China, and South Africa (BRICS), which account for approximately 60% of cases globally.2 Even more alarming are cases of extensively drug-resistant TB (XDR-TB), defined as TB resistant to isoniazid, rifampin, any fluoroquinolone, and any second-line injectable agent, which account for 9% of cases of MDR-TB.2 Whereas TB is usually responsive to a standard 2-month regimen of isoniazid,
rifampin, pyrazinamide, and ethambutol, followed by a 4-month regimen of isoniazid and rifampin, MDR and XDR-TB require more intensive and more prolonged regimens, with second-line agents and up to 6 drugs, including injectables.3,4 These regimens are generally considered less effective, more toxic, and more expensive.5,6 Recently, a meta-analysis showed only a 44% success rate using second-line agents in patients with XDR-TB with a mortality rate ranging between 14 and 27%.7 In the presence of HIV co-infection, the mortality rate exceeded 70%.8 Thus, the development of new agents that may shorten the duration
1
Palm Beach Atlantic University, West Palm Beach, FL, USA Lebanese American University, Byblos, Lebanon
2
Corresponding Author: Hanine Mansour, School of Pharmacy, Lebanese American University, PO Box: 36–S 23, Byblos, Lebanon. Email: [email protected]
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of therapy, improve adherence, decrease the risk of relapse, reduce mortality, and control the MDR-TB epidemic is warranted.3,9 This article provides a comprehensive clinical review on bedaquiline fumarate (Sirturo, Janssen Products, LP), a novel oral diarylquinoline antimycobacterial agent active against Mycobacterium tuberculosis, including MDR strains.10 It was formerly known as R207910 and TMC207 and was originally developed through a partnership between Tibotec and the TB Alliance.11,12 On December 28, 2012, the FDA granted bedaquiline fast approval and an “orphan drug” designation to treat adults with MDR pulmonary TB as part of a combination therapy when an effective treatment regimen cannot otherwise be provided.13 Bedaquiline was approved based on phase 2 data using time to sputum culture conversion as a surrogate marker for clinical efficacy.13 Additional studies are currently being conducted to further evaluate its safety and efficacy in the treatment of MDR-TB.14
Data Sources A search of PubMed (January 2004-May 2013) and International Pharmaceutical Abstracts (January 2004-May 2013) using the search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. All data available in English were reviewed. Supplementary sources included proceedings of the Union World Conference on Lung Health and information available from the manufacturer’s Web site.
Bedaquiline fumarate Chemical Formula: C36H35BrN2O6 Molecular Weight: 671.5769
Pharmacology and Chemistry Bedaquiline belongs to a new class of antimycobacterial agents known as diarylquinolines.10 It exerts a bactericidal and sterilizing activity against M tuberculosis and selected nontuberculous mycobacteria by inhibiting the adenosine triphosphate (ATP) synthase.3 Bedaquiline targets the central region of the c subunit of the enzyme, halting the energy production process and inhibiting the mycobacterium reproduction, resulting in its death.3,11,15 Unlike in many other bacteria, ATP synthase is essential for the optimal growth of M tuberculosis, and any mutation in the c subunit can lead to resistance to bedaquiline.10,11 The chemical name of bedaquiline (Figure 1) is (1R, 2S)-1-(6-bromo-2methoxy-3-quinolinyl)-4-dimethylamino)-2-(1naphthalenyl)-1-phenyl-2-butanol.16 It is compounded with fumaric acid (1:1) as bedaquiline fumarate (Figure 1).17
Bedaquiline Chemical Formula: C32H31BrN2O2 Molecular Weight: 555.50474
Microbiology Bedaquiline displays potent in vitro activity against both drug-susceptible and drug-resistant isolates of M tuberculosis with minimum inhibitory concentrations (MICs) in the
Figure 1. Chemical structures of bedaquiline fumarate and bedaquiline.
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Chahine et al Table 1. In Vitro Activity of Bedaquilinea Against Mycobacterium tuberculosis.18,19 Organism M tuberculosis Drug susceptibleb,c Multidrug resistantb,c
Isolates, n 41 44
Range of MICs (µg/mL) 0.002-0.12 0.004-0.13
a
Susceptibility to bedaquiline was determined using an agar dilution method. b MIC50 = minimum inhibitory concentration for 50% of tested isolates = 0.03 µg/mL. c MIC90 = minimum inhibitory concentration for 90% of tested isolates = 0.06 µg/mL.
Table 2. In Vitro Activity of Bedaquilinea Against Nontuberculous Mycobacterium Species.11,18,19 Organism Mycobacterium avium complexb M abscessusc M chelonae M conspicuum M fortuitum M gordonae M hiberniae M interjectum M kansasii M mageritense M malmoense M marinumd M phlei M simiae M smegmatis M scrofulaceum M szulgai M terrae M ulceranse M vaccae
Table 3. In Vitro Activity of Bedaquilinea Against Different Gram-Negative and -Positive Bacteria.18
Isolates, n
Range of MICs (µg/mL)
22
0.03-0.25
1 3 1 3 1 1 1 1 1 1 1 2 2 7 1 2 2 1 2
NR 0.06-0.5 0.13 0.13-0.25 0.03 0.03 0.03 0.03 0.03 0.5 NR 0.03-0.13 0.03 0.003-0.01 0.03 0.03-0.06 0.03-0.13 NR 0.03
Abbreviations: MIC50, minimum inhibitory concentration for 50% of tested isolates; NR, not reported; MIC90, minimum inhibitory concentration for 90% of tested isolates. a Susceptibility to bedaquiline was determined using an agar dilution method. b MIC50 = 0.03 µg/mL; MIC90 = 0.13 µg/mL. c Median MIC = 0.25 µg/mL. d Median MIC = 0.003 µg/mL. e Median MIC = 0.5 µg/mL.
range of 0.002 to 0.13 µg/mL (Table 1).18,19 It also exhibits bactericidal activity against dormant nonreplicating tubercle bacilli.11 Bedaquiline displays potent in vitro activity against nontuberculous mycobacteria (Table 2).18,19 Three species of nontuberculous mycobacteria were found to be
Organism Corynebacterium jeikeium C urealyticum Helicobacter pylori Nocardia asteroids N farcinia Escherichia coli Haemophilus influenza Streptococcus pneumoniae Staphylococcus aureus
Isolates, n 1 1 20 1 1 1 1 10 1
Range of MIC99
2 to >4
16-64
MIC50 (µg/mL) 4 4 4 >16 >16 >32 >32 >32 >32
Abbreviations: MIC50 = minimum inhibitory concentration for 50% of tested isolates; MIC99 = minimum inhibitory concentration for 99% of tested isolates. a Susceptibility to bedaquiline was determined using the standard CLSI (Clinical and Laboratory Standards Institute) method of susceptibility testing.
intrinsically resistant to bedaquiline: M novocastrense (MIC of 8.0 µg/mL), M shimoidei (MIC of 8.0 µg/mL), and M xenopi (MIC 4.0-8.0 µg/mL).19 Bedaquiline showed bactericidal activity against M leprae in a murine leprosy model.20 Bedaquiline appears to have a narrow spectrum of activity targeted against Mycobacterium species because it displays weak activity against Gram-positive and Gramnegative bacteria (Table 3).18
Resistance The binding site of bedaquiline is in proximity to the amino acid residue Glu61 whose carboxyl group is protonated during proton translocation of the ATP synthase. Mutations in positions 63 and 66 impede bedaquiline’s access to its target at residue 61, causing either intrinsic (as in M xenopi) or acquired (as in M tuberculosis) resistance.21 The proportion of naturally occurring resistant mutants is low and estimated as 1 strain over 107/108 bacteria.18 M tuberculosis develops resistance to bedaquiline as a result of missense mutations of the atpE gene that disrupts the capacity of bedaquiline to bind to the c subunit of the F0 domain of the ATP synthase. The mutation either occurs at position 63 with a proline substituting alanine or at position 66 with a methionine substituting a leucine.11,18,22 M segmatis develops resistance to bedaquiline as a result of a mutation at position 32 with valine substituting asparagine.18 Nontuberculous mycobacteria develop resistance to bedaquiline as a result of a mutation at position 63 with methionine substituting alanine. Bedaquiline, as opposed to quinolones, does not seem to be subject to mutations within the DNA gyrase regions gyrA and gyrB.18
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Table 4. Bedaquiline Plasma Pharmacokinetics Parameters for Oral 25-, 100-, and 400-mg Daily Doses for 7 Days in Humans.10,28 Daily Dosea
Cmax (µg/mL)
tmax (h)
AUC0-24 (µg h/mL)
25 mg 0.32 ± 0.09 3.93 (2.00-6.17) 3.97 ± 1.29 100 mg 1.21 ± 0.39 4 (1.97-8.00) 16.05 ± 5.07 400 mg 5.50 ± 2.96 4 (2.05-6.02) 64.75 ± 20.7
Effective t1/2 (hours) 24 24 24
Abbreviations: Cmax, maximum concentration; tmax, time to Cmax; AUC0-24, area under the concentration-time curve from 0 to 24 hours; t1/2, elimination half-life. a Administered as a daily oral dose for 7 days.
Pharmacokinetics Plasma pharmacokinetic parameters for bedaquiline administered orally are listed in Table 4. The maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curve (AUC) increased proportionally with increased doses of bedaquiline, which displays a linear pharmacokinetic profile up to doses of 700 mg.18 The relative bioavailability of bedaquiline increases by about 2-fold with the administration of a standard meal containing approximately 22 g of fat as compared with administration on an empty stomach.10 Plasma concentrations were not affected by body weight, with data available only for patients with a body mass index of 14.1 to 26.9 kg/m2.23 The plasma protein binding of bedaquiline is higher than 99.9%. The volume of distribution in the central compartment is estimated to be approximately 164 L. In a murine model of TB, bedaquiline and its N-monodesmethyl metabolite (M2) were extensively distributed in the lungs, with AUC168h lung/plasma ratios of about 20 for bedaquiline and 100 to 200 for its metabolite.24 Bedaquiline is metabolized by CYP3A4 of the cytochrome P450 system and is primarily oxidized to its active M2, which has 4- to 6-fold lower antimycobacterial potency and lower average exposure (23% to 31%) than the parent drug.10,11,25 Bedaquiline is primarily eliminated in the feces. Less than 0.001% of the administered dose is eliminated unchanged in the urine. After reaching Cmax, bedaquiline concentrations decline triexponentially with time.18 This provides a rationale for less-frequent dosing regimens and for combining bedaquiline with other drugs with long half-lives.25 The mean terminal elimination half-life (t1/2) of bedaquiline and M2 is approximately 5.5 months and is independent of the administered dose.11,18,26 This prolonged elimination likely reflects the slow release of bedaquiline and M2 from peripheral tissues, which may accumulate and cause phospholipidosis.26
Pharmacodynamics The exact pharmacokinetic-pharmacodynamic parameter that best correlates with bedaquiline has not been well
elucidated. However, recent studies have shown that AUC is the primary activity driver of bedaquiline.24,27 In a study of early bactericidal activity (EBA) in treatment-naïve patients with smear-positive TB, oral bedaquiline at doses of 25, 100, and 400 mg had almost no bactericidal activity during days 2 to 4 of therapy.28 This may correlate with the interruption of cellular energy hemostasis. Bedaquiline showed bactericidal activity between days 4 to 7, with an overall decrease in mycobacterial colony counts of only 0.77 log10 colony-forming units (CFU). These results are confirmed by a phase 2 study, where the decrease of mycobacterial CFU of bedaquiline 400 mg orally was 0.57 log10 up to 7 days of therapy. The drug’s bactericidal activity was improved between weeks 1 and 4 suggesting a time-dependent killing.23 In contrast, the EBA of bedaquiline appeared to increase with doses up to 400 mg daily and was established following 2 loading doses and given for 14 days even at a low dose of 100 mg daily.27 Late bactericidal activity of bedaquiline against dormant or nonreplicating bacilli has the potential of shortening the duration of therapy.29 In a murine model of TB, bedaquiline demonstrated a greater bactericidal activity intracellularly in the peritoneal macrophage than on the extracellular bacilli because the preliminary static phase was shorter or absent.30 In another murine model, bedaquiline was shown to possess significant sterilizing activity, and the substitution of bedaquiline for isoniazid or its addition to the standard anti-TB regimen allowed for reduction of the treatment duration to 4 months.31 Bedaquiline displayed a synergistic effect with pyrazinamide-containing regimens in clearing bacterial counts in the lungs of mice after only 2 months of therapy.32 The 14-day EBA of bedaquiline was also reported in treatmentnaïve patients with drug-susceptible uncomplicated TB.33 M2 is not thought to contribute significantly to clinical efficacy but appears to correlate with QT prolongation.10
Clinical Trials Phase 2 Studies The first study, TMC207-208, was designed in 2 stages: an exploratory stage followed by a proof-of-efficacy stage.23,26,27,34-36 The first stage consisted of a multicenter, placebo-controlled, double-blind, randomized trial that was conducted to assess safety and efficacy of bedaquiline in hospitalized adult patients with pulmonary MDR-TB in South Africa.23,26 Exclusion criteria included isolates not susceptible to aminoglycosides (other than streptomycin) and fluoroquinolones, previous treatment for MDR-TB, neurological or severe extrapulmonary manifestations of TB, HIV positive with a CD4+ count fewer than 300 cells/ µL, receipt of antiretrovirals or antifungals in the previous 90 days, and significant cardiac arrhythmia. Patients were randomized into 2 groups. The first group consisted of 23
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Chahine et al patients who received bedaquiline 400 mg orally daily for 2 weeks, followed by 200 mg 3 times a week for 6 weeks in combination with a standard 5-drug regimen for the treatment of MDR-TB. The second group consisted of 24 patients who received placebo for 8 weeks in combination with a standard 5-drug regimen for the treatment of MDR-TB. The preferred standard regimen consisted of 5 second-line agents: kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or terizidone. Modifications to the background regimen were allowed according to culture and sensitivity results as well as tolerance to and availability of the medications. After completing 8 weeks of therapy with either bedaquiline or placebo, both groups continued to receive their background regimen and were followed up for a total of 2 years. It is important to note that the 8-week duration of therapy with bedaquiline in this trial was shorter than the 24-week duration of therapy approved by the FDA. The primary end point was the time to conversion of sputum cultures, in liquid broth, from positive to negative, which was defined as the interval between the date of treatment initiation and the date of the first of at least 2 consecutive negative weekly cultures. The secondary end point was the change from baseline in the log10 count of organism CFUs. The median age of patients was 33 years; 74% were male, 55% were black, 13% were HIV positive, and 85% had cavitation in at least 1 lung. At week 8, the time for conversion to a negative sputum culture was significantly reduced in the bedaquiline group compared with the placebo group using the Cox regression analysis: hazard ratio (HR) = 11.8; 95% CI = 2.3 to 61.3; P = .003. At week 8, the rates of conversion to a negative culture were 48% in the bedaquiline group and 9% in the placebo group, which results in a significant difference of 39%; 95% CI = 12.3 to 63.1; P = .004. The median log10 count also declined more rapidly in the bedaquiline group than in the placebo group. During the 2-year follow-up, 23 patients discontinued throughout the course of the study: 10 from the bedaquiline group and 13 from the placebo group. Investigators cited noncompliance and the rigorous program of investigations for safety as reasons for discontinuation from the study. At week 24, the time for conversion to a negative sputum culture remained significantly reduced in the bedaquiline group compared with the placebo group, using the Cox regression analysis: HR = 2.253; 95% CI = 1.08 to 4.71; P = .031. However, the rates of conversion to a negative culture were 81% in the bedaquiline group and 65.2% in the placebo group, which resulted in a nonstatistically significant difference of 15.8%; 95% CI = −11.9 to 41.9; P = .32. At week 104, the rate of treatment success was 52.4% in the bedaquiline group and 47.8% in the placebo group; the P value was not provided. It is important to note that during this trial, 1 patient in the bedaquiline group (4.8%) acquired resistance to companion drugs compared with 5 patients in the
placebo group (21.7%); however, the difference did not reach statistical significance; P = .18. The second stage of the study as reported in 2 webinars was similar in design to the first stage but included patients from Brazil, India, Latvia, Peru, Philippines, Russia, South Africa, and Thailand. Patients were randomized into 2 groups.34,35 The first group consisted of 80 patients and received bedaquiline 400 mg orally once daily for the first 2 weeks and 200 mg 3 times per week for the following 22 weeks, in addition to a standard background regimen for the treatment of MDR-TB. The second group consisted of 81 patients and received a placebo for 24 weeks in addition to a standard background regimen for the treatment of MDR-TB. The preferred background regimen was the same regimen used in the first stage of the study. Both groups continued to receive their background regimen for a total duration of 18 to 24 months. The primary efficacy end point was time to sputum culture conversion, in liquid broth, defined as 2 consecutive negative cultures collected at least 25 days apart and not followed by a confirmed positive culture. The secondary efficacy end point was culture conversion rate at week 24. The median age was 31 for the bedaquiline group and 35 for the placebo group; 66% were male in the bedaquiline group versus 61% in the placebo group; 9% were HIV positive in the bedaquiline group and 18% in the placebo group. Efficacy analyses were based on the modified intention-to-treat population (mITT), which included 132 patients. The median time to sputum conversion was 12 weeks in the bedaquiline group and 18 weeks in the placebo group; P = .003. At week 24, the sputum conversion rate was 79% in the bedaquiline group and 58% in the placebo group; P = .008. The addition of bedaquiline to a background regimen for the treatment of MDR-TB resulted in a faster and a higher culture conversion rate. An analysis on all patients who completed 72 weeks of treatment was conducted to compare the antibacterial and sterilizing activities of the bedaquiline group compared with the placebo group and to compare culture conversion rates.35 During the 72 weeks of follow-up, 57 patients discontinued throughout the course of the study—27 from the bedaquiline group and 30 from the placebo group. Investigators cited adverse events, withdrawal of consent, noncompliance, and ineligibility or loss to follow-up as reasons for discontinuation from the study. Looking at the mITT population, the median time to sputum conversion was 86 days for the bedaquiline group and 168 days for the placebo group; P = .029. Looking at all available data at week 88, the rates of conversion to a negative culture were 66.7% in the bedaquiline group and 47% in the placebo group, which resulted in a difference of 19.7%; P = .021.35 TMC207-209,36 the second phase 2 study, was a multicenter phase 2 open-label study conducted to assess the safety and efficacy of bedaquiline in the treatment of adults with MDR-TB, including those with pre-XDR-TB and
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XDR-TB from China, Estonia, Latvia, Peru, Philippines, Russia, South Korea, South Africa, Thailand, Turkey, and Ukraine. Pre-XDR-TB was defined as resistance to either a fluoroquinolone or a second-line injectable drug. Exclusion criteria included severe extrapulmonary manifestations of TB, HIV positive with a CD4+ count fewer than 250 cells/ µL, and receipt of certain antiretrovirals. Patients received bedaquiline 400 mg orally daily for 14 days, followed by 200 mg 3 times a week for 22 weeks in addition to an optimized background regimen that included fluoroquinolones, ethionamide/protionamide, pyrazinamide, aminoglycosides, cycloserine/terizodone, and ethambutol. Patients continued to receive the background regimen for 18 to 24 months, and modifications to the background regimen were allowed. The primary end point was the time to sputum culture conversion in liquid broth. Efficacy analyses were based on the mITT, which included 205 patients. The median age was 32 years; 64% were male; 5% were HIV positive; 54% had MDR-TB; 25% had pre-XDR-TB; and 21% had XDR-TB. The median time to culture conversion was 8 weeks, and the conversion rate at week 24 was 79.5%. In the subset of patients with MDR-TB, the median time to culture conversion was 8 weeks, and the conversion rate at week 24 was 87.1%. In the subset of patients with preXDR-TB, the median time to culture conversion was 12 weeks, and the conversion rate at week 24 was 77.3%. Finally, in the subset of patients with XDR-TB, the median time to culture conversion was 24 weeks, and the conversion rate at week 24 was 55.6%.
Phase 3 Studies A phase 3 placebo-controlled, double-blind, randomized trial of 600 adults with smear-positive MDR or pre-XDRTB is being planned to provide safety and efficacy data for bedaquiline; however, the study is not yet open for participant recruitment.14 The first arm is scheduled to receive bedaquiline 400 mg daily for the first 2 weeks and 200 mg 3 times a week for 22 weeks in combination with a background regimen for the treatment of MDR-TB. The second arm is scheduled to receive placebo in combination with the same background regimen for the treatment of MDR-TB. Patients will be followed for 84 weeks, and the primary end point is the number of patients with favorable outcome at week 60.14,35 Another phase 3 study is currently being conducted to evaluate early access of bedaquiline to adults with smear-positive pre-XDR or XDR-TB.14
Safety, Warnings, and Precautions Bedaquiline was studied as part of a combination regimen for the treatment of MDR-TB.26,27,34-36 As a consequence, most of the side effects observed during clinical trials are known to occur in patients receiving second-line agents for
the treatment of MDR-TB: anorexia, arthralgia, chest pain, headache, hemoptysis, increase in amylase, increase in transaminases, nausea, and rash.10 There are no contraindications to the use of the drug.10 However, bedaquiline was associated with an increased risk of unexplained mortality (boxed warning), restricting its use to when no other regimen can be provided.10 Bedaquiline was also associated with an increased risk of QT prolongation (boxed warning) requiring ECG monitoring before initiation of treatment and at least at 2, 12, and 24 weeks after starting treatment and requiring drug discontinuation in the presence of clinically significant ventricular arrhythmia or when QTcF (QT interval corrected using Fridericia’s formula) exceeds 500 ms.10 Bedaquiline was also associated with hepatic-related adverse events, requiring drug discontinuation in the presence of significant or persistent increase in aminotransferases.10 Specifically, increases in transaminases and blood amylase were reported more frequently in the bedaquiline group (8.9% and 2.5%, respectively) than in the placebo group (1.2% and 1.2%, respectively).10 Safety data from the first stage of TMC207-208 revealed that the most common adverse events associated with the bedaquiline group were nausea (26.1%), extremity pain (17.4%), bilateral hearing impairment (13.0%), acne (8.7%), and chest pain (4.3%).27 Nausea and increases in the mean QTcF were the only adverse events that occurred significantly more frequently in the bedaquiline arm than in the placebo arm.27 Safety data from the second stage of TMC207-208 revealed that the most common adverse events associated with the bedaquiline group were nausea (34%), arthralgia (34%), headache (27%), hyperuricemia (25%), vomiting (25%), hemoptysis (19%), pruritus (13%), insomnia (13%), dizziness (11%), abdominal pain (11%), back pain (10%), and pyrexia (10%).34 Adverse events, including nausea and increases in the mean QTcF, were evenly distributed across treatment groups.34 However, a secondary analysis of TMC207-208 revealed 10 deaths in the bedaquiline arm compared with 2 deaths in the placebo arm, and the difference was statistically significant.37 The exact cause of this difference in mortality is unknown. Finally, safety data from TMC207-209 revealed that the most common adverse events associated with the bedaquiline group were hyperuricemia (14%), arthralgia (12%), and nausea (11%).36
Drug Interactions Because bedaquiline is metabolized by CYP3A4, its blood concentration and therapeutic effect may be altered by coadministration with CYP3A4 inducers or inhibitors. Coadministration of bedaquiline 300 mg daily and rifampin 600 mg daily for 21 days to healthy individuals resulted in significant reduction of AUC to bedaquiline (52%), rendering the drug potentially ineffective; therefore, clinicians should avoid combining bedaquiline with strong CYP3A4
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Chahine et al inducers, such as rifampin, rifabutin, and rifapentine.10 Coadministration of bedaquiline 400 mg daily for 14 days and ketoconazole 400 mg daily for 4 days to healthy individuals resulted in an increase of AUC to bedaquiline (22%), rendering the drug potentially toxic; therefore, clinicians should avoid combining bedaquiline with strong CYP3A4 inhibitors for more than 14 consecutive days unless the benefit outweighs the risk.10 Coadministration of bedaquiline 400 mg daily for 14 days and isoniazid 300 mg daily plus pyrazinamide 1000 mg daily for 5 days to healthy individuals did not result in significant changes of AUC to bedaquiline, isoniazid, or pyrazinamide; therefore, dosage adjustment is not necessary when combining bedaquiline with isoniazid and pyrazinamide.10 During clinical trials, the administration of bedaquiline with ethambutol, kanamycin, pyrazinamide, ofloxacin, and cycloserine to patients with MDR-TB did not result in any significant drug-drug interactions.10 Therefore, and with the exception of rifamycins, bedaquiline can be safely administered with other TB agents without dosage adjustment. Coadministration of bedaquiline 400 mg, single dose, and lopinavir 400 mg plus ritonavir 100 mg twice daily for 24 days to healthy individuals resulted in increase of AUC to bedaquiline (22%), rendering the drug potentially toxic; therefore, clinicians should use bedaquiline with lopinavir plus ritonavir only if the benefits outweigh the risks.10 Coadministration of bedaquiline 400 mg single dose and nevirapine 200 mg twice daily for 28 days to patients with HIV did not result in significant changes of AUC to bedaquiline; therefore, bedaquiline can be safely administered with nevirapine without dosage adjustment.10 Coadministration of bedaquiline 400 mg, single dose, on day 1 and another 400 mg, single dose, on day 29 and efavirenz 600 mg daily from day 15 to 28 to healthy individuals did not result in significant pharmacokinetic interactions, suggesting that the effect of efavirenz on single-dose bedaquiline is unlikely to be clinically significant.38 However, coadministration of bedaquiline 400 mg, single dose, on day 1 and another 400 mg, single dose, on day 43 and efavirenz 600 mg daily from day 15 to 42 to healthy individuals provided a model where investigators predicted a 52% reduction in the average steady-state concentrations of bedaquiline with chronic administration and proposed one of the following adjustments to the bedaquiline regimen: 400 mg daily for 2 weeks followed by 200 mg daily for 22 weeks or 400 mg daily for 2 weeks followed by 400 mg 3 times weekly for 22 weeks.39 Finally, coadministration of bedaquiline with ketoconazole resulted in a synergistic effect on QTc interval prolongation.10 Coadministration of bedaquiline with clofazimine also resulted in an increased QTc interval.10 This may increase the risk of arrhythmias, including torsades de pointes.
Availability, Dosage, and Administration Bedaquiline is supplied as 100-mg tablets.10 The recommended dose for the current FDA-approved indication of MDR-TB as part of combination therapy in adults (≥18 years) is 400 mg administered orally once daily for the first 2 weeks and 200 mg 3 times per week thereafter for a total of 24 weeks.10 Bedaquiline should be administered with food by directly observed therapy.10 An FDA-approved medication guide should be dispensed with this medication.10
Special Populations The safety and efficacy of bedaquiline are not yet established in the pediatric and geriatric populations.10 Although bedaquiline is classified as pregnancy category B, it should be used during pregnancy only if clearly indicated because human data are not available.10 It is not known whether bedaquiline is excreted in breast milk; therefore, its use in nursing mothers involves weighing the benefits of the drug to the mother and the risk of adverse reactions to the infant.10 No dosage adjustment is necessary in patients with mild to moderate hepatic or renal impairment.10 Bedaquiline should be used with caution in patients with severe hepatic or renal impairment and in patients undergoing dialysis because it has not been well studied in this population.10
Formulary Considerations Because cases of MDR-TB are currently rare in the United States where only 98 cases occurred in 2011, the use of bedaquiline is likely to be limited at least for the near future; however, the proportion of new cases of MDR-TB has increased from 0.9% in 2008 to 1.3% in 2011.40 In other parts of the world, TB and specifically MDR-TB are more prevalent, particularly in the BRICS countries.2 As of October 2012 and according to the WHO, 84 countries reported at least 1 case of XDR-TB.2 Hence bedaquiline represents an important addition to the armamentarium of agents against TB in these countries. Evidence from phase 2 studies showed faster sputum conversion rates with bedaquiline than placebo. This may shorten the duration of treatment, improve adherence, achieve higher cure rates, and preserve the activity of the background regimen.41 However, concerns regarding increased mortality restrict bedaquiline use to cases where no alternative options are possible. QT prolongation also limits bedaquiline use in patients with cardiac conduction abnormalities and in patients receiving other QT-prolonging agents, such as macrolides, fluoroquinolones, and azole antifungals. CYP3A4 interactions warrant patient monitoring, particularly when bedaquiline is concomitantly prescribed with rifamycins and/or antiretrovirals. Finally, the cost of a 24-week course of therapy with bedaquiline is $36 000.00 (average wholesale price),
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which is higher than the cost of other second-line agents commonly used in the treatment of MDR-TB.42
Conclusions Bedaquiline, a first-in-class diarylquinoline, was shown to be effective in combination with other agents for the treatment of adults with pulmonary MDR-TB. It is the first anti-TB agent to be approved by the FDA in more than 40 years. The novelty of the drug is in its unique mechanism of action, wherein it inhibits the proton pump activity of ATP synthase in M tuberculosis. Bedaquiline has shown promising results in phase 2 clinical studies; however, it has been associated with several adverse events, including nausea, arthralgia, headache, hemoptysis, and chest pain. In addition, bedaquiline has 2 boxed warnings for increased mortality and QT prolongation and a warning regarding hepatic-related adverse reactions. Also, it has serious drug interactions with CYP3A4 inducers and inhibitors and other QT-prolonging agents. Phase 3 studies are definitely needed to further evaluate its safety, efficacy, and tolerability in patients with TB. If proven safe and effective, bedaquiline will be particularly useful in areas of the world where MDR-TB is prevalent but with careful monitoring for adverse effects and drug interactions, although its cost may represent a burden in resource-limited countries. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Chahine serves on the speakers’ bureaus for Forest Pharmaceuticals, Inc, and Optimer Pharmaceuticals, Inc. Drs Karaoui and Mansour have nothing to disclose.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. World Health Organization. Tuberculosis fact sheets. http:// www.who.int/mediacentre/factsheets/fs104/en/. Accessed May 7, 2012. 2. World Health Organization. Multidrug-resistant tuberculosis (MDR-TB): 2012 update. http://www.who.int/tb/publications/MDRFactSheet2012.pdf. Accessed May 7, 2013. 3. Singh H, Natt NK, Garewal N, Pugazhenthan T. Bedaquiline: a new weapon against MDR and XDR-TB. Int J Basic Clin Pharmacol. 2013;2:96-102. 4. Sotgiu G, Ferrara G, Matteelli A, et al. Epidemiology and clinical management of XDR-TB: a systematic review by TBNET. Eur Respir J. 2009;33:871-881. 5. Diel R, Rutz S, Castell S, Schaberg T. Tuberculosis: cost of illness in Germany. Eur Respir J. 2012;40:143-151. 6. Loddenkemper R, Sotgiu G, Mitnick CD. Cost of tuberculosis in the era of multidrug resistance: will it become unaffordable? Eur Respir J. 2012;40:9-11.
7. Jacobson KR, Tierney DB, Jeon CY, Mitnick CD, Murray MB. Treatment outcomes among patients with extensively drug-resistant tuberculosis:systematic review and meta-analysis. Clin Infect Dis. 2010;51:6-14. 8. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients coinfected with tuberculosis and HIV in a rural area of South Africa. Lancet. 2006;368:1575-1580. 9. Mitchison AD. Shortening the treatment of tuberculosis: a new diarylquinoline drug promises faster treatment for tuberculosis. Nat Biotechnol. 2005;23:187-188. 10. Sirturo (bedaquiline) [product information]. Titusville, NJ: Janssen Therapeutics; 2012. 11. Matteelli A, Carvahlo AC, Dooley KE, Kritski A. TMC207: the first compound of a new class of potent anti-tuberculosis drugs. Future Microbiol. 2010;5:849-858. 12. Protopopova M, Bogatcheva E, Nikonenko B, et al. In search of new cures for tuberculosis. Med Chem. 2007;3:301-316. 13. FDA news release [untitled]. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm333695. htm. Accessed May 7, 2013. 14. Bedaquiline clinical trials. http://www.clinicaltrials.gov/ct2/ results?term=bedaquiline. Accessed May 7, 2013. 15. Gumbo T. TMC207 (R207910). In: Bruten LL, Chabner BA, Knollmann BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw Hill; 2011:1561. 16. Bedaquiline: compound summary. http://pubchem.ncbi.nlm. nih.gov/summary/summary.cgi?cid=5388906&loc=ec_rcs. Accessed May 22, 2013. 17. Bedaquiline fumarate: compound summary. http://pubchem. ncbi.nlm.nih.gov/summary/summary.cgi?cid=56841861. Accessed May 18, 2013. 18. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 2005;307:223-227. 19. Huitric E, Verhasselt P, Andries K, Hoffner E. In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2007;51: 4202-4204. 20. Ji B, Chauffour A, Andries K, Jarlier V. Bactericidal activities of R207910 and other newer antimicrobial agents against Mycobacterium leprae in mice. Antimicrob Agents Chemother. 2006;50:1558-1560. 21. 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;50:2853-2856. 22. Cole ST, Alzari PM. TB: a new target, a new drug. Science. 2005;307:214-215. 23. Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009;360:2397-2405. 24. 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. Leibert E, Rom WN. New drugs and regimens for treatment of TB. Expert Rev Anti Infect Ther. 2010;8:801-813.
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Chahine et al 26. Diacon AH, Donald PR, Pym A, et al. 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;56:3271-3276. 27. Diacon AH, Dawson R, Von Groote-Bidlingmaier F, et al. Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis. Antimicrob Agents Chemother. 2013;57:2199-2203. 28. Rustomjee R, Diacon AH, Allen J, et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob Agents Chemother. 2008;52:2831-2835. 29. 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;50:3543-3547. 30. Dhillon J, Andries K, Phillips PJP, Mitchison DA. Bactericidal activity of the diarylquinoline TMC207 against Mycobacterium tuberculosis outside and within cells. Tuberculosis. 2010;90:301-305. 31. 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;180:553-557. 32. Ibrahim M, Andries K, Lounis N, et al. Synergistic activity of R207910 combined with pyrazinamide against murine tuberculosis. Antimicrob Agents Chemother. 2007;51:1011-1015. 33. Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. 14-Day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet. 2012;380:986-993. 34. McNeely DF, Diacon AH, Pym A, et al. TMC-207 versus placebo plus OBT for the treatment of MDR-TB: a prospective clinical trial. Oral Presentation at: 41st Union World Conference on Lung Health; November 13, 2010; Berlin, Germany. http://uwclh.conference2web.com/content/187?from_ view=all&view_address=search%3Dmcneeley%26events%3
D1%26groups%3D1%26sessions%3D35. Accessed May 30, 2013. 35. Haxaire M, TMC207 Team, Diacon AH, et al. Use of bedaquiline (TMC207) for the treatment of MDR-TB. Data presented at: 43rd Union World Conference on Lung Health; November 16, 2012; Kuala Lumpur, Malaysia. http://uwclh.conference2web.com/content/2168/details?from_view=all&view_add ress=search%3Dhaxaire%26events%3D3%26sessions %3D301. Accessed May 30, 2013. 36. Haxaire M, TMC207 Team, Diacon AH, et al. Phase 2 openlabel trial of TMC207 in an MDR-TB treatment regimen. Data presented at: 42nd Union World Conference on Lung Health; October 30, 2011; Lille, France. http://uwclh.conference2web. com/content/1108/details?from_view=all&view_address=sea rch%3Dhaxaire%26events%3D2. Accessed May 30, 2013. 37. Anti-Infective Drugs Advisory Committee Meeting Briefing Document TMC207 (bedaquiline) Treatment of Patients with MDR-TB. http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ Anti-InfectiveDrugsAdvisoryCommittee/UCM329260.pdf. Accessed May 31, 2013. 38. Dooley KE, Park JG, Swindells S, et al; ACTG 5267 Study Team. Safety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group Study A5267. J Acquir Immune Defic Syndr. 2012;59:455-462. 39. Svensson EM, Aweeka F, Park JG, Marzan F, Dooley KE, Karlsson MO. Model-based estimates of the effects of efavirenz on bedaquiline pharmacokinetics and suggested dose adjustments for patients coinfected with HIV and tuberculosis. Antimicrob Agents Chemother. 2013;57:2780-2787. 40. Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 2011. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2012. http://www.cdc.gov/ tb/statistics/reports/2011. Accessed May 7, 2013. 41. Cohen J. Approval of novel TB drug celebrated-with restraint. Science. 2013;339:130. 42. Red Book Online. http://www.redbook.com/redbook/online. Accessed September 13, 2013.
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research-article2013
AOPXXX10.1177/1060028013504087Annals of PharmacotherapyChahine et al
Review Article-New Drug Approvals
Bedaquiline: A Novel Diarylquinoline for Multidrug-Resistant Tuberculosis
Annals of Pharmacotherapy 2014, Vol. 48(1) 107–115 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013504087 aop.sagepub.com
Elias B. Chahine, PharmD, BCPS (AQ-ID)1, Lamis R. Karaoui, PharmD, BCPS2, and Hanine Mansour, PharmD, BCPS2
Abstract Objective: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, dosage, and administration of bedaquiline, a novel oral diarylquinoline antimycobacterial agent approved by the Food and Drug Administration for the treatment of adults with pulmonary multidrug-resistant tuberculosis (MDR-TB). Data Sources: A search of PubMed (January 2004-May 2013) and International Pharmaceutical Abstracts (January 2004May 2013) using the search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included proceedings of the Union World Conference on Lung Health. Study Selection and Data Extraction: Preclinical data as well as Phase 1 and 2 studies published in English were evaluated. Data Synthesis: Bedaquiline possesses a unique mechanism of action that disrupts the activity of the mycobacterial adenosine triphosphate synthase. Clinical trials have been conducted evaluating the use of bedaquiline in combination with a background regimen for the treatment of adults with pulmonary MDR-TB. Bedaquiline has an excellent in vitro activity against Mycobacterium tuberculosis, including multidrug resistant M tuberculosis; however, its side effect profile limits its use against MDR-TB when no other effective regimen can be provided. Bedaquiline carries Black Box warnings for increased risk of unexplained mortality and QT prolongation. Bedaquiline is metabolized via the CYP3A4 isoenzyme and thus interacts with rifamycins and several antiretrovirals. Conclusions: In an era of emerging resistance and given the suboptimal efficacy and toxicity of currently available regimens for MDR-TB, bedaquiline represents a great addition to the existing armamentarium of anti-TB agents particularly in areas of the world where the disease is endemic. Keywords bedaquiline, diarylquinoline, antimycobacterial, multi-drug resistant tuberculosis, MDR-TB.
Tuberculosis (TB) remains a major threat, killing millions of people every year around the world. According to the World Health Organization (WHO), in 2011, 8.7 million people were diagnosed with TB, and 1.4 million died from TB-related causes.1 Although the number of TB-infected patients is decreasing, the worldwide burden is still high and the WHO statistics related to the emergence of resistant strains of mycobacteria are alarming.1 According to a WHO estimate, 3.7% of new TB patients has multidrugresistant TB (MDR-TB) defined as TB resistant to both isoniazid and rifampin.2 MDR-TB has emerged as a global public health issue, particularly in Brazil, Russia, India, China, and South Africa (BRICS), which account for approximately 60% of cases globally.2 Even more alarming are cases of extensively drug-resistant TB (XDR-TB), defined as TB resistant to isoniazid, rifampin, any fluoroquinolone, and any second-line injectable agent, which account for 9% of cases of MDR-TB.2 Whereas TB is usually responsive to a standard 2-month regimen of isoniazid,
rifampin, pyrazinamide, and ethambutol, followed by a 4-month regimen of isoniazid and rifampin, MDR and XDR-TB require more intensive and more prolonged regimens, with second-line agents and up to 6 drugs, including injectables.3,4 These regimens are generally considered less effective, more toxic, and more expensive.5,6 Recently, a meta-analysis showed only a 44% success rate using second-line agents in patients with XDR-TB with a mortality rate ranging between 14 and 27%.7 In the presence of HIV co-infection, the mortality rate exceeded 70%.8 Thus, the development of new agents that may shorten the duration
1
Palm Beach Atlantic University, West Palm Beach, FL, USA Lebanese American University, Byblos, Lebanon
2
Corresponding Author: Hanine Mansour, School of Pharmacy, Lebanese American University, PO Box: 36–S 23, Byblos, Lebanon. Email: [email protected]
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of therapy, improve adherence, decrease the risk of relapse, reduce mortality, and control the MDR-TB epidemic is warranted.3,9 This article provides a comprehensive clinical review on bedaquiline fumarate (Sirturo, Janssen Products, LP), a novel oral diarylquinoline antimycobacterial agent active against Mycobacterium tuberculosis, including MDR strains.10 It was formerly known as R207910 and TMC207 and was originally developed through a partnership between Tibotec and the TB Alliance.11,12 On December 28, 2012, the FDA granted bedaquiline fast approval and an “orphan drug” designation to treat adults with MDR pulmonary TB as part of a combination therapy when an effective treatment regimen cannot otherwise be provided.13 Bedaquiline was approved based on phase 2 data using time to sputum culture conversion as a surrogate marker for clinical efficacy.13 Additional studies are currently being conducted to further evaluate its safety and efficacy in the treatment of MDR-TB.14
Data Sources A search of PubMed (January 2004-May 2013) and International Pharmaceutical Abstracts (January 2004-May 2013) using the search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. All data available in English were reviewed. Supplementary sources included proceedings of the Union World Conference on Lung Health and information available from the manufacturer’s Web site.
Bedaquiline fumarate Chemical Formula: C36H35BrN2O6 Molecular Weight: 671.5769
Pharmacology and Chemistry Bedaquiline belongs to a new class of antimycobacterial agents known as diarylquinolines.10 It exerts a bactericidal and sterilizing activity against M tuberculosis and selected nontuberculous mycobacteria by inhibiting the adenosine triphosphate (ATP) synthase.3 Bedaquiline targets the central region of the c subunit of the enzyme, halting the energy production process and inhibiting the mycobacterium reproduction, resulting in its death.3,11,15 Unlike in many other bacteria, ATP synthase is essential for the optimal growth of M tuberculosis, and any mutation in the c subunit can lead to resistance to bedaquiline.10,11 The chemical name of bedaquiline (Figure 1) is (1R, 2S)-1-(6-bromo-2methoxy-3-quinolinyl)-4-dimethylamino)-2-(1naphthalenyl)-1-phenyl-2-butanol.16 It is compounded with fumaric acid (1:1) as bedaquiline fumarate (Figure 1).17
Bedaquiline Chemical Formula: C32H31BrN2O2 Molecular Weight: 555.50474
Microbiology Bedaquiline displays potent in vitro activity against both drug-susceptible and drug-resistant isolates of M tuberculosis with minimum inhibitory concentrations (MICs) in the
Figure 1. Chemical structures of bedaquiline fumarate and bedaquiline.
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Chahine et al Table 1. In Vitro Activity of Bedaquilinea Against Mycobacterium tuberculosis.18,19 Organism M tuberculosis Drug susceptibleb,c Multidrug resistantb,c
Isolates, n 41 44
Range of MICs (µg/mL) 0.002-0.12 0.004-0.13
a
Susceptibility to bedaquiline was determined using an agar dilution method. b MIC50 = minimum inhibitory concentration for 50% of tested isolates = 0.03 µg/mL. c MIC90 = minimum inhibitory concentration for 90% of tested isolates = 0.06 µg/mL.
Table 2. In Vitro Activity of Bedaquilinea Against Nontuberculous Mycobacterium Species.11,18,19 Organism Mycobacterium avium complexb M abscessusc M chelonae M conspicuum M fortuitum M gordonae M hiberniae M interjectum M kansasii M mageritense M malmoense M marinumd M phlei M simiae M smegmatis M scrofulaceum M szulgai M terrae M ulceranse M vaccae
Table 3. In Vitro Activity of Bedaquilinea Against Different Gram-Negative and -Positive Bacteria.18
Isolates, n
Range of MICs (µg/mL)
22
0.03-0.25
1 3 1 3 1 1 1 1 1 1 1 2 2 7 1 2 2 1 2
NR 0.06-0.5 0.13 0.13-0.25 0.03 0.03 0.03 0.03 0.03 0.5 NR 0.03-0.13 0.03 0.003-0.01 0.03 0.03-0.06 0.03-0.13 NR 0.03
Abbreviations: MIC50, minimum inhibitory concentration for 50% of tested isolates; NR, not reported; MIC90, minimum inhibitory concentration for 90% of tested isolates. a Susceptibility to bedaquiline was determined using an agar dilution method. b MIC50 = 0.03 µg/mL; MIC90 = 0.13 µg/mL. c Median MIC = 0.25 µg/mL. d Median MIC = 0.003 µg/mL. e Median MIC = 0.5 µg/mL.
range of 0.002 to 0.13 µg/mL (Table 1).18,19 It also exhibits bactericidal activity against dormant nonreplicating tubercle bacilli.11 Bedaquiline displays potent in vitro activity against nontuberculous mycobacteria (Table 2).18,19 Three species of nontuberculous mycobacteria were found to be
Organism Corynebacterium jeikeium C urealyticum Helicobacter pylori Nocardia asteroids N farcinia Escherichia coli Haemophilus influenza Streptococcus pneumoniae Staphylococcus aureus
Isolates, n 1 1 20 1 1 1 1 10 1
Range of MIC99
2 to >4
16-64
MIC50 (µg/mL) 4 4 4 >16 >16 >32 >32 >32 >32
Abbreviations: MIC50 = minimum inhibitory concentration for 50% of tested isolates; MIC99 = minimum inhibitory concentration for 99% of tested isolates. a Susceptibility to bedaquiline was determined using the standard CLSI (Clinical and Laboratory Standards Institute) method of susceptibility testing.
intrinsically resistant to bedaquiline: M novocastrense (MIC of 8.0 µg/mL), M shimoidei (MIC of 8.0 µg/mL), and M xenopi (MIC 4.0-8.0 µg/mL).19 Bedaquiline showed bactericidal activity against M leprae in a murine leprosy model.20 Bedaquiline appears to have a narrow spectrum of activity targeted against Mycobacterium species because it displays weak activity against Gram-positive and Gramnegative bacteria (Table 3).18
Resistance The binding site of bedaquiline is in proximity to the amino acid residue Glu61 whose carboxyl group is protonated during proton translocation of the ATP synthase. Mutations in positions 63 and 66 impede bedaquiline’s access to its target at residue 61, causing either intrinsic (as in M xenopi) or acquired (as in M tuberculosis) resistance.21 The proportion of naturally occurring resistant mutants is low and estimated as 1 strain over 107/108 bacteria.18 M tuberculosis develops resistance to bedaquiline as a result of missense mutations of the atpE gene that disrupts the capacity of bedaquiline to bind to the c subunit of the F0 domain of the ATP synthase. The mutation either occurs at position 63 with a proline substituting alanine or at position 66 with a methionine substituting a leucine.11,18,22 M segmatis develops resistance to bedaquiline as a result of a mutation at position 32 with valine substituting asparagine.18 Nontuberculous mycobacteria develop resistance to bedaquiline as a result of a mutation at position 63 with methionine substituting alanine. Bedaquiline, as opposed to quinolones, does not seem to be subject to mutations within the DNA gyrase regions gyrA and gyrB.18
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Table 4. Bedaquiline Plasma Pharmacokinetics Parameters for Oral 25-, 100-, and 400-mg Daily Doses for 7 Days in Humans.10,28 Daily Dosea
Cmax (µg/mL)
tmax (h)
AUC0-24 (µg h/mL)
25 mg 0.32 ± 0.09 3.93 (2.00-6.17) 3.97 ± 1.29 100 mg 1.21 ± 0.39 4 (1.97-8.00) 16.05 ± 5.07 400 mg 5.50 ± 2.96 4 (2.05-6.02) 64.75 ± 20.7
Effective t1/2 (hours) 24 24 24
Abbreviations: Cmax, maximum concentration; tmax, time to Cmax; AUC0-24, area under the concentration-time curve from 0 to 24 hours; t1/2, elimination half-life. a Administered as a daily oral dose for 7 days.
Pharmacokinetics Plasma pharmacokinetic parameters for bedaquiline administered orally are listed in Table 4. The maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curve (AUC) increased proportionally with increased doses of bedaquiline, which displays a linear pharmacokinetic profile up to doses of 700 mg.18 The relative bioavailability of bedaquiline increases by about 2-fold with the administration of a standard meal containing approximately 22 g of fat as compared with administration on an empty stomach.10 Plasma concentrations were not affected by body weight, with data available only for patients with a body mass index of 14.1 to 26.9 kg/m2.23 The plasma protein binding of bedaquiline is higher than 99.9%. The volume of distribution in the central compartment is estimated to be approximately 164 L. In a murine model of TB, bedaquiline and its N-monodesmethyl metabolite (M2) were extensively distributed in the lungs, with AUC168h lung/plasma ratios of about 20 for bedaquiline and 100 to 200 for its metabolite.24 Bedaquiline is metabolized by CYP3A4 of the cytochrome P450 system and is primarily oxidized to its active M2, which has 4- to 6-fold lower antimycobacterial potency and lower average exposure (23% to 31%) than the parent drug.10,11,25 Bedaquiline is primarily eliminated in the feces. Less than 0.001% of the administered dose is eliminated unchanged in the urine. After reaching Cmax, bedaquiline concentrations decline triexponentially with time.18 This provides a rationale for less-frequent dosing regimens and for combining bedaquiline with other drugs with long half-lives.25 The mean terminal elimination half-life (t1/2) of bedaquiline and M2 is approximately 5.5 months and is independent of the administered dose.11,18,26 This prolonged elimination likely reflects the slow release of bedaquiline and M2 from peripheral tissues, which may accumulate and cause phospholipidosis.26
Pharmacodynamics The exact pharmacokinetic-pharmacodynamic parameter that best correlates with bedaquiline has not been well
elucidated. However, recent studies have shown that AUC is the primary activity driver of bedaquiline.24,27 In a study of early bactericidal activity (EBA) in treatment-naïve patients with smear-positive TB, oral bedaquiline at doses of 25, 100, and 400 mg had almost no bactericidal activity during days 2 to 4 of therapy.28 This may correlate with the interruption of cellular energy hemostasis. Bedaquiline showed bactericidal activity between days 4 to 7, with an overall decrease in mycobacterial colony counts of only 0.77 log10 colony-forming units (CFU). These results are confirmed by a phase 2 study, where the decrease of mycobacterial CFU of bedaquiline 400 mg orally was 0.57 log10 up to 7 days of therapy. The drug’s bactericidal activity was improved between weeks 1 and 4 suggesting a time-dependent killing.23 In contrast, the EBA of bedaquiline appeared to increase with doses up to 400 mg daily and was established following 2 loading doses and given for 14 days even at a low dose of 100 mg daily.27 Late bactericidal activity of bedaquiline against dormant or nonreplicating bacilli has the potential of shortening the duration of therapy.29 In a murine model of TB, bedaquiline demonstrated a greater bactericidal activity intracellularly in the peritoneal macrophage than on the extracellular bacilli because the preliminary static phase was shorter or absent.30 In another murine model, bedaquiline was shown to possess significant sterilizing activity, and the substitution of bedaquiline for isoniazid or its addition to the standard anti-TB regimen allowed for reduction of the treatment duration to 4 months.31 Bedaquiline displayed a synergistic effect with pyrazinamide-containing regimens in clearing bacterial counts in the lungs of mice after only 2 months of therapy.32 The 14-day EBA of bedaquiline was also reported in treatmentnaïve patients with drug-susceptible uncomplicated TB.33 M2 is not thought to contribute significantly to clinical efficacy but appears to correlate with QT prolongation.10
Clinical Trials Phase 2 Studies The first study, TMC207-208, was designed in 2 stages: an exploratory stage followed by a proof-of-efficacy stage.23,26,27,34-36 The first stage consisted of a multicenter, placebo-controlled, double-blind, randomized trial that was conducted to assess safety and efficacy of bedaquiline in hospitalized adult patients with pulmonary MDR-TB in South Africa.23,26 Exclusion criteria included isolates not susceptible to aminoglycosides (other than streptomycin) and fluoroquinolones, previous treatment for MDR-TB, neurological or severe extrapulmonary manifestations of TB, HIV positive with a CD4+ count fewer than 300 cells/ µL, receipt of antiretrovirals or antifungals in the previous 90 days, and significant cardiac arrhythmia. Patients were randomized into 2 groups. The first group consisted of 23
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Chahine et al patients who received bedaquiline 400 mg orally daily for 2 weeks, followed by 200 mg 3 times a week for 6 weeks in combination with a standard 5-drug regimen for the treatment of MDR-TB. The second group consisted of 24 patients who received placebo for 8 weeks in combination with a standard 5-drug regimen for the treatment of MDR-TB. The preferred standard regimen consisted of 5 second-line agents: kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or terizidone. Modifications to the background regimen were allowed according to culture and sensitivity results as well as tolerance to and availability of the medications. After completing 8 weeks of therapy with either bedaquiline or placebo, both groups continued to receive their background regimen and were followed up for a total of 2 years. It is important to note that the 8-week duration of therapy with bedaquiline in this trial was shorter than the 24-week duration of therapy approved by the FDA. The primary end point was the time to conversion of sputum cultures, in liquid broth, from positive to negative, which was defined as the interval between the date of treatment initiation and the date of the first of at least 2 consecutive negative weekly cultures. The secondary end point was the change from baseline in the log10 count of organism CFUs. The median age of patients was 33 years; 74% were male, 55% were black, 13% were HIV positive, and 85% had cavitation in at least 1 lung. At week 8, the time for conversion to a negative sputum culture was significantly reduced in the bedaquiline group compared with the placebo group using the Cox regression analysis: hazard ratio (HR) = 11.8; 95% CI = 2.3 to 61.3; P = .003. At week 8, the rates of conversion to a negative culture were 48% in the bedaquiline group and 9% in the placebo group, which results in a significant difference of 39%; 95% CI = 12.3 to 63.1; P = .004. The median log10 count also declined more rapidly in the bedaquiline group than in the placebo group. During the 2-year follow-up, 23 patients discontinued throughout the course of the study: 10 from the bedaquiline group and 13 from the placebo group. Investigators cited noncompliance and the rigorous program of investigations for safety as reasons for discontinuation from the study. At week 24, the time for conversion to a negative sputum culture remained significantly reduced in the bedaquiline group compared with the placebo group, using the Cox regression analysis: HR = 2.253; 95% CI = 1.08 to 4.71; P = .031. However, the rates of conversion to a negative culture were 81% in the bedaquiline group and 65.2% in the placebo group, which resulted in a nonstatistically significant difference of 15.8%; 95% CI = −11.9 to 41.9; P = .32. At week 104, the rate of treatment success was 52.4% in the bedaquiline group and 47.8% in the placebo group; the P value was not provided. It is important to note that during this trial, 1 patient in the bedaquiline group (4.8%) acquired resistance to companion drugs compared with 5 patients in the
placebo group (21.7%); however, the difference did not reach statistical significance; P = .18. The second stage of the study as reported in 2 webinars was similar in design to the first stage but included patients from Brazil, India, Latvia, Peru, Philippines, Russia, South Africa, and Thailand. Patients were randomized into 2 groups.34,35 The first group consisted of 80 patients and received bedaquiline 400 mg orally once daily for the first 2 weeks and 200 mg 3 times per week for the following 22 weeks, in addition to a standard background regimen for the treatment of MDR-TB. The second group consisted of 81 patients and received a placebo for 24 weeks in addition to a standard background regimen for the treatment of MDR-TB. The preferred background regimen was the same regimen used in the first stage of the study. Both groups continued to receive their background regimen for a total duration of 18 to 24 months. The primary efficacy end point was time to sputum culture conversion, in liquid broth, defined as 2 consecutive negative cultures collected at least 25 days apart and not followed by a confirmed positive culture. The secondary efficacy end point was culture conversion rate at week 24. The median age was 31 for the bedaquiline group and 35 for the placebo group; 66% were male in the bedaquiline group versus 61% in the placebo group; 9% were HIV positive in the bedaquiline group and 18% in the placebo group. Efficacy analyses were based on the modified intention-to-treat population (mITT), which included 132 patients. The median time to sputum conversion was 12 weeks in the bedaquiline group and 18 weeks in the placebo group; P = .003. At week 24, the sputum conversion rate was 79% in the bedaquiline group and 58% in the placebo group; P = .008. The addition of bedaquiline to a background regimen for the treatment of MDR-TB resulted in a faster and a higher culture conversion rate. An analysis on all patients who completed 72 weeks of treatment was conducted to compare the antibacterial and sterilizing activities of the bedaquiline group compared with the placebo group and to compare culture conversion rates.35 During the 72 weeks of follow-up, 57 patients discontinued throughout the course of the study—27 from the bedaquiline group and 30 from the placebo group. Investigators cited adverse events, withdrawal of consent, noncompliance, and ineligibility or loss to follow-up as reasons for discontinuation from the study. Looking at the mITT population, the median time to sputum conversion was 86 days for the bedaquiline group and 168 days for the placebo group; P = .029. Looking at all available data at week 88, the rates of conversion to a negative culture were 66.7% in the bedaquiline group and 47% in the placebo group, which resulted in a difference of 19.7%; P = .021.35 TMC207-209,36 the second phase 2 study, was a multicenter phase 2 open-label study conducted to assess the safety and efficacy of bedaquiline in the treatment of adults with MDR-TB, including those with pre-XDR-TB and
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XDR-TB from China, Estonia, Latvia, Peru, Philippines, Russia, South Korea, South Africa, Thailand, Turkey, and Ukraine. Pre-XDR-TB was defined as resistance to either a fluoroquinolone or a second-line injectable drug. Exclusion criteria included severe extrapulmonary manifestations of TB, HIV positive with a CD4+ count fewer than 250 cells/ µL, and receipt of certain antiretrovirals. Patients received bedaquiline 400 mg orally daily for 14 days, followed by 200 mg 3 times a week for 22 weeks in addition to an optimized background regimen that included fluoroquinolones, ethionamide/protionamide, pyrazinamide, aminoglycosides, cycloserine/terizodone, and ethambutol. Patients continued to receive the background regimen for 18 to 24 months, and modifications to the background regimen were allowed. The primary end point was the time to sputum culture conversion in liquid broth. Efficacy analyses were based on the mITT, which included 205 patients. The median age was 32 years; 64% were male; 5% were HIV positive; 54% had MDR-TB; 25% had pre-XDR-TB; and 21% had XDR-TB. The median time to culture conversion was 8 weeks, and the conversion rate at week 24 was 79.5%. In the subset of patients with MDR-TB, the median time to culture conversion was 8 weeks, and the conversion rate at week 24 was 87.1%. In the subset of patients with preXDR-TB, the median time to culture conversion was 12 weeks, and the conversion rate at week 24 was 77.3%. Finally, in the subset of patients with XDR-TB, the median time to culture conversion was 24 weeks, and the conversion rate at week 24 was 55.6%.
Phase 3 Studies A phase 3 placebo-controlled, double-blind, randomized trial of 600 adults with smear-positive MDR or pre-XDRTB is being planned to provide safety and efficacy data for bedaquiline; however, the study is not yet open for participant recruitment.14 The first arm is scheduled to receive bedaquiline 400 mg daily for the first 2 weeks and 200 mg 3 times a week for 22 weeks in combination with a background regimen for the treatment of MDR-TB. The second arm is scheduled to receive placebo in combination with the same background regimen for the treatment of MDR-TB. Patients will be followed for 84 weeks, and the primary end point is the number of patients with favorable outcome at week 60.14,35 Another phase 3 study is currently being conducted to evaluate early access of bedaquiline to adults with smear-positive pre-XDR or XDR-TB.14
Safety, Warnings, and Precautions Bedaquiline was studied as part of a combination regimen for the treatment of MDR-TB.26,27,34-36 As a consequence, most of the side effects observed during clinical trials are known to occur in patients receiving second-line agents for
the treatment of MDR-TB: anorexia, arthralgia, chest pain, headache, hemoptysis, increase in amylase, increase in transaminases, nausea, and rash.10 There are no contraindications to the use of the drug.10 However, bedaquiline was associated with an increased risk of unexplained mortality (boxed warning), restricting its use to when no other regimen can be provided.10 Bedaquiline was also associated with an increased risk of QT prolongation (boxed warning) requiring ECG monitoring before initiation of treatment and at least at 2, 12, and 24 weeks after starting treatment and requiring drug discontinuation in the presence of clinically significant ventricular arrhythmia or when QTcF (QT interval corrected using Fridericia’s formula) exceeds 500 ms.10 Bedaquiline was also associated with hepatic-related adverse events, requiring drug discontinuation in the presence of significant or persistent increase in aminotransferases.10 Specifically, increases in transaminases and blood amylase were reported more frequently in the bedaquiline group (8.9% and 2.5%, respectively) than in the placebo group (1.2% and 1.2%, respectively).10 Safety data from the first stage of TMC207-208 revealed that the most common adverse events associated with the bedaquiline group were nausea (26.1%), extremity pain (17.4%), bilateral hearing impairment (13.0%), acne (8.7%), and chest pain (4.3%).27 Nausea and increases in the mean QTcF were the only adverse events that occurred significantly more frequently in the bedaquiline arm than in the placebo arm.27 Safety data from the second stage of TMC207-208 revealed that the most common adverse events associated with the bedaquiline group were nausea (34%), arthralgia (34%), headache (27%), hyperuricemia (25%), vomiting (25%), hemoptysis (19%), pruritus (13%), insomnia (13%), dizziness (11%), abdominal pain (11%), back pain (10%), and pyrexia (10%).34 Adverse events, including nausea and increases in the mean QTcF, were evenly distributed across treatment groups.34 However, a secondary analysis of TMC207-208 revealed 10 deaths in the bedaquiline arm compared with 2 deaths in the placebo arm, and the difference was statistically significant.37 The exact cause of this difference in mortality is unknown. Finally, safety data from TMC207-209 revealed that the most common adverse events associated with the bedaquiline group were hyperuricemia (14%), arthralgia (12%), and nausea (11%).36
Drug Interactions Because bedaquiline is metabolized by CYP3A4, its blood concentration and therapeutic effect may be altered by coadministration with CYP3A4 inducers or inhibitors. Coadministration of bedaquiline 300 mg daily and rifampin 600 mg daily for 21 days to healthy individuals resulted in significant reduction of AUC to bedaquiline (52%), rendering the drug potentially ineffective; therefore, clinicians should avoid combining bedaquiline with strong CYP3A4
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Chahine et al inducers, such as rifampin, rifabutin, and rifapentine.10 Coadministration of bedaquiline 400 mg daily for 14 days and ketoconazole 400 mg daily for 4 days to healthy individuals resulted in an increase of AUC to bedaquiline (22%), rendering the drug potentially toxic; therefore, clinicians should avoid combining bedaquiline with strong CYP3A4 inhibitors for more than 14 consecutive days unless the benefit outweighs the risk.10 Coadministration of bedaquiline 400 mg daily for 14 days and isoniazid 300 mg daily plus pyrazinamide 1000 mg daily for 5 days to healthy individuals did not result in significant changes of AUC to bedaquiline, isoniazid, or pyrazinamide; therefore, dosage adjustment is not necessary when combining bedaquiline with isoniazid and pyrazinamide.10 During clinical trials, the administration of bedaquiline with ethambutol, kanamycin, pyrazinamide, ofloxacin, and cycloserine to patients with MDR-TB did not result in any significant drug-drug interactions.10 Therefore, and with the exception of rifamycins, bedaquiline can be safely administered with other TB agents without dosage adjustment. Coadministration of bedaquiline 400 mg, single dose, and lopinavir 400 mg plus ritonavir 100 mg twice daily for 24 days to healthy individuals resulted in increase of AUC to bedaquiline (22%), rendering the drug potentially toxic; therefore, clinicians should use bedaquiline with lopinavir plus ritonavir only if the benefits outweigh the risks.10 Coadministration of bedaquiline 400 mg single dose and nevirapine 200 mg twice daily for 28 days to patients with HIV did not result in significant changes of AUC to bedaquiline; therefore, bedaquiline can be safely administered with nevirapine without dosage adjustment.10 Coadministration of bedaquiline 400 mg, single dose, on day 1 and another 400 mg, single dose, on day 29 and efavirenz 600 mg daily from day 15 to 28 to healthy individuals did not result in significant pharmacokinetic interactions, suggesting that the effect of efavirenz on single-dose bedaquiline is unlikely to be clinically significant.38 However, coadministration of bedaquiline 400 mg, single dose, on day 1 and another 400 mg, single dose, on day 43 and efavirenz 600 mg daily from day 15 to 42 to healthy individuals provided a model where investigators predicted a 52% reduction in the average steady-state concentrations of bedaquiline with chronic administration and proposed one of the following adjustments to the bedaquiline regimen: 400 mg daily for 2 weeks followed by 200 mg daily for 22 weeks or 400 mg daily for 2 weeks followed by 400 mg 3 times weekly for 22 weeks.39 Finally, coadministration of bedaquiline with ketoconazole resulted in a synergistic effect on QTc interval prolongation.10 Coadministration of bedaquiline with clofazimine also resulted in an increased QTc interval.10 This may increase the risk of arrhythmias, including torsades de pointes.
Availability, Dosage, and Administration Bedaquiline is supplied as 100-mg tablets.10 The recommended dose for the current FDA-approved indication of MDR-TB as part of combination therapy in adults (≥18 years) is 400 mg administered orally once daily for the first 2 weeks and 200 mg 3 times per week thereafter for a total of 24 weeks.10 Bedaquiline should be administered with food by directly observed therapy.10 An FDA-approved medication guide should be dispensed with this medication.10
Special Populations The safety and efficacy of bedaquiline are not yet established in the pediatric and geriatric populations.10 Although bedaquiline is classified as pregnancy category B, it should be used during pregnancy only if clearly indicated because human data are not available.10 It is not known whether bedaquiline is excreted in breast milk; therefore, its use in nursing mothers involves weighing the benefits of the drug to the mother and the risk of adverse reactions to the infant.10 No dosage adjustment is necessary in patients with mild to moderate hepatic or renal impairment.10 Bedaquiline should be used with caution in patients with severe hepatic or renal impairment and in patients undergoing dialysis because it has not been well studied in this population.10
Formulary Considerations Because cases of MDR-TB are currently rare in the United States where only 98 cases occurred in 2011, the use of bedaquiline is likely to be limited at least for the near future; however, the proportion of new cases of MDR-TB has increased from 0.9% in 2008 to 1.3% in 2011.40 In other parts of the world, TB and specifically MDR-TB are more prevalent, particularly in the BRICS countries.2 As of October 2012 and according to the WHO, 84 countries reported at least 1 case of XDR-TB.2 Hence bedaquiline represents an important addition to the armamentarium of agents against TB in these countries. Evidence from phase 2 studies showed faster sputum conversion rates with bedaquiline than placebo. This may shorten the duration of treatment, improve adherence, achieve higher cure rates, and preserve the activity of the background regimen.41 However, concerns regarding increased mortality restrict bedaquiline use to cases where no alternative options are possible. QT prolongation also limits bedaquiline use in patients with cardiac conduction abnormalities and in patients receiving other QT-prolonging agents, such as macrolides, fluoroquinolones, and azole antifungals. CYP3A4 interactions warrant patient monitoring, particularly when bedaquiline is concomitantly prescribed with rifamycins and/or antiretrovirals. Finally, the cost of a 24-week course of therapy with bedaquiline is $36 000.00 (average wholesale price),
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which is higher than the cost of other second-line agents commonly used in the treatment of MDR-TB.42
Conclusions Bedaquiline, a first-in-class diarylquinoline, was shown to be effective in combination with other agents for the treatment of adults with pulmonary MDR-TB. It is the first anti-TB agent to be approved by the FDA in more than 40 years. The novelty of the drug is in its unique mechanism of action, wherein it inhibits the proton pump activity of ATP synthase in M tuberculosis. Bedaquiline has shown promising results in phase 2 clinical studies; however, it has been associated with several adverse events, including nausea, arthralgia, headache, hemoptysis, and chest pain. In addition, bedaquiline has 2 boxed warnings for increased mortality and QT prolongation and a warning regarding hepatic-related adverse reactions. Also, it has serious drug interactions with CYP3A4 inducers and inhibitors and other QT-prolonging agents. Phase 3 studies are definitely needed to further evaluate its safety, efficacy, and tolerability in patients with TB. If proven safe and effective, bedaquiline will be particularly useful in areas of the world where MDR-TB is prevalent but with careful monitoring for adverse effects and drug interactions, although its cost may represent a burden in resource-limited countries. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Chahine serves on the speakers’ bureaus for Forest Pharmaceuticals, Inc, and Optimer Pharmaceuticals, Inc. Drs Karaoui and Mansour have nothing to disclose.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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