Mechanism Of Action
Bedaquiline is a diarylquinoline antimycobacterial drug [see Microbiology].
Bedaquiline is primarily subjected to oxidative metabolism leading to the formation of N–monodesmethyl
metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given
its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (4-fold to 6-
fold lower) compared to the parent compound. However, M2 plasma concentrations appeared to
correlate with QT prolongation.
In Study 1, the mean increases in QTcF, corrected using the Fridericia method, were greater in the
SIRTURO treatment group compared to the placebo treatment group from the first week of treatment
(9.9 ms at Week 1 for SIRTURO and 3.5 ms for placebo). The largest mean increase in QTcF during the
24 weeks of SIRTURO treatment was 15.7 ms compared to 6.2 ms with placebo treatment (at Week 18).
After bedaquiline treatment ended, the QTcF gradually decreased, and the mean value was similar to that
in the placebo group by study week 60.
In Study 3, where patients with no treatment options received other QT-prolonging drugs used to treat
tuberculosis, including clofazimine, concurrent use with SIRTURO resulted in additive QTcF
prolongation, proportional to the number of QT prolonging drugs in the treatment regimen. Patients
taking SIRTURO alone with no other QT prolonging drug developed a mean QTcF increase over
baseline of 23.7 ms with no QTcF segment duration in excess of 480 ms, whereas patients taking at least
2 other QT prolonging drugs developed a mean QTcF prolongation of 30.7 ms over baseline, and
resulted in QTcF segment duration in excess of 500 ms in one patient. [See WARNINGS AND PRECAUTIONS]
After oral administration of SIRTURO maximum plasma concentrations (Cmax ) are typically achieved at
approximately 5 hours post-dose. Cmax and the area under the plasma concentration-time curve (AUC)
increased proportionally up to the highest doses studied [700 mg single-dose (1.75 times the 400 mg
loading dose)] [see DOSAGE AND ADMINISTRATION]. Administration of SIRTURO with a standard meal
containing approximately 22 grams of fat (558 total Kcal) increased the relative bioavailability by about
2-fold compared to administration under fasted conditions. Therefore, SIRTURO should be taken with
food to enhance its oral bioavailability.
The plasma protein binding of bedaquiline is greater than 99.9%. The volume of distribution in the
central compartment is estimated to be approximately 164 Liters.
CYP3A4 was the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the
formation of the N-monodesmethyl metabolite (M2), which is 4 to 6-times less active in terms of
After reaching Cmax , bedaquiline concentrations decline tri-exponentially. The mean terminal
elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5
months. This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from
Based on preclinical studies, bedaquiline is mainly eliminated in feces. The urinary excretion of
unchanged bedaquiline was less than or equal to 0.001% of the dose in clinical studies, indicating that
renal clearance of unchanged drug is insignificant.
After single-dose administration of 400 mg SIRTURO to 8 patients with moderate
hepatic impairment (Child-Pugh B), mean exposure to bedaquiline and M2 (AUC672h ) was
approximately 20% lower compared to healthy subjects. SIRTURO has not been studied in patients with
severe hepatic impairment. [See WARNINGS AND PRECAUTIONS and Use In Specific Populations].
SIRTURO has mainly been studied in patients with normal renal function. Renal
excretion of unchanged bedaquiline is not substantial (less than or equal to 0.001%).
In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO 200 mg three
times per week, creatinine clearance was not found to influence the pharmacokinetic parameters of
bedaquiline. It is therefore not expected that mild or moderate renal impairment will have a clinically
relevant effect on the exposure to bedaquiline. However, in patients with severe renal impairment or
end-stage renal disease requiring hemodialysis or peritoneal dialysis bedaquiline concentrations may be
increased due to alteration of drug absorption, distribution, and metabolism secondary to renal
dysfunction. As bedaquiline is highly bound to plasma proteins, it is unlikely that it will be significantly
removed from plasma by hemodialysis or peritoneal dialysis [see Use In Specific Populations].
In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO no clinically
relevant difference in exposure between men and women were observed.
In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO,
systemic exposure (AUC) to bedaquiline was found to be 34% lower in Black patients than in patients
from other race categories. This lower exposure was not considered to be clinically relevant as no
clear relationship between exposure to bedaquiline and response has been observed in clinical trials of
MDR-TB. Furthermore, response rates were comparable in patients of different race categories that
completed 24 weeks of bedaquiline treatment.
There are limited data on the use of SIRTURO in HIV co-infected patients [see DRUG INTERACTIONS].
There are limited data on the use of SIRTURO in tuberculosis patients 65 years
In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO, age was not
found to influence the pharmacokinetics of bedaquiline.
The pharmacokinetics of SIRTURO in pediatric patients have not been evaluated.
In vitro, bedaquiline does not significantly inhibit the activity of the following CYP450 enzymes that
were tested: CYP1A2, CYP2A6, CYP2C8/9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A4/5
and CYP4A, and it does not induce CYP1A2, CYP2C9, CYP2C19, or CYP3A4 activities.
Bedaquiline is an in vitro substrate of CYP3A4, and because of this, the following clinical drug
interaction studies were performed.
Co-administration of multiple-dose bedaquiline (400 mg once daily for 14 days) and
multiple-dose ketoconazole (once daily 400 mg for 4 days) in healthy subjects increased the AUC24h ,
Cmax and Cmin of bedaquiline by 22% [90% CI (12; 32)], 9% [90% CI (-2, 21)] and 33% [90% CI (24,
43)] respectively [see DRUG INTERACTIONS].
In a drug interaction study of single-dose 300 mg bedaquiline and multiple-dose rifampin
(once daily 600 mg for 21 days) in healthy subjects, the exposure (AUC) to bedaquiline was reduced by
52% [90% CI (-57; -46)] [see DRUG INTERACTIONS].
The combination of multiple-dose bedaquiline 400 mg once daily with multipledose
isoniazid/pyrazinamide (300 mg/2000 mg once daily) in healthy subjects did not result in clinically
relevant changes in the exposure (AUC) to bedaquiline, isoniazid or pyrazinamide [see DRUG INTERACTIONS].
In a placebo-controlled study in patients with MDR-TB, no major impact of co-administration of
bedaquiline on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine
In a drug interaction study in healthy volunteers of single-dose bedaquiline (400 mg)
and multiple-dose lopinavir (400 mg)/ritonavir (100 mg) given twice daily for 24 days, the mean AUC
of bedaquiline was increased by 22% [90% CI (11; 34)] while the mean Cmax was not substantially
affected [see DRUG INTERACTIONS].
Co-administration of multiple-dose nevirapine 200 mg twice daily for 4 weeks in HIVinfected
patients with a single 400 mg dose of bedaquiline did not result in clinically relevant changes
in the exposure to bedaquiline [see DRUG INTERACTIONS].
Co-administration of a single dose of bedaquiline 400 mg and efavirenz 600 mg daily for 27
days to healthy volunteers resulted in approximately a 20% decrease in the AUCinf of bedaquiline; the
Cmax of bedaquiline was not altered. The AUC and Cmax of the primary metabolite of bedaquiline (M2)
were increased by 70% and 80%, respectively. The effect of efavirenz on the pharmacokinetics of
bedaquiline and M2 following steady-state administration of bedaquiline has not been evaluated [see DRUG INTERACTIONS].
Mechanism Of Action
SIRTURO is a diarylquinoline antimycobacterial drug that inhibits mycobacterial ATP (adenosine 5’-
triphosphate) synthase, by binding to subunit c of the enzyme that is essential for the generation of
energy in M. tuberculosis.
A potential for development of resistance to bedaquiline in M. tuberculosis exists. Modification of the
atpE target gene, and/or upregulation of the MmpS5-MmpL5 efflux pump have been associated with
increased bedaquiline MIC values in isolates of M. tuberculosis. Target-based mutations generated in
preclinical studies lead to 8- to 133-fold increases in bedaquiline MIC, resulting in MICs ranging from
0.25 to 4.0 micrograms per mL. Efflux-based mutations have been seen in preclinical and clinical
isolates. These lead to 2- to 8-fold increases in bedaquiline MICs, resulting in bedaquiline MICs
ranging from 0.25 to 0.50 micrograms per mL.
M. tuberculosis isolates from a clinical study in patients with MDR-TB that developed at least 4-fold
increase in bedaquiline MIC were associated with mutations in Rv0678 gene that lead to upregulation of
the MmpS5-MmpL5 efflux pump. Isolates with these efflux-based mutations are less susceptible to
Activity In Vitro And In Clinical Infections
SIRTURO has been shown to be active in vitro and in clinical infections against most isolates of M.
tuberculosis [see INDICATIONS and Clinical Studies].
Susceptibility Test Methods
In vitro susceptibility tests should be performed according to published methods1,2,3 , and a MIC value
should be reported. However, no correlation was seen between the culture conversion rates at Week 24
and baseline MICs in clinical studies (Table 2) and susceptibility test interpretive criteria for
bedaquiline cannot be established at this time. A specialist in drug-resistant TB should be consulted in
evaluating therapeutic options.
When susceptibility testing is performed by 7H9 broth microdilution or agar methods, a range of
concentrations from 0.008 microgram per mL to 2.0 micrograms per mL should be assessed. The
minimum inhibitory concentration (MIC) should be determined as the lowest concentration of
bedaquiline that results in complete inhibition of growth by either agar or broth methods. All assays
should be performed in polystyrene plates or tubes. Löwenstein-Jensen (LJ) medium should not be used
for the susceptibility testing. Bedaquiline working solution should be prepared in dimethylsulfoxide
(DMSO). An inoculum of approximately 105 colony forming units/mL should be used for both liquid
and solid media.
The bedaquiline agar (left) and resazurin microtiter assay (REMA; a 7H9 broth microdilution to which
resazurin, a bacterial growth indicator, was added) (right) MIC distributions against clinical isolates
resistant to isoniazid and rifampin from Studies 1, 2, and 3 are provided below.
Figure 1: Bedaquiline MIC Distribution against Baseline MDR -TB Isolates from Studies 1, 2, and 3
mITT Subjects: Agar Method (left) and Broth (REMA) Method (right)
MICs for baseline M. tuberculosis isolates from subjects in Studies 1 and 3 and their sputum culture
conversion rates at Week 24 are shown in Table 2 below. Based on the available data, there was no
trend for poor microbiologic outcomes related to baseline bedaquiline MIC.
Table 2: Culture Conversion Rates (Week 24 Data Selection, No
Overruling for Discontinuation) at Week 24 By Baseline Bedaquiline
MIC for mITT Subjects from Study 1 and Study 3
|SIRTURO (Bedaquiline) Treatment Group
24-Week Culture Conversion Rate
||7H9 Broth (REMA)
|N=number of subjects with data; n=number of subjects with that result;
MIC=minimum inhibitory concentration; BR=background regimen
Nineteen patients in the efficacy population of study 3 had bedaquiline susceptibility testing results of
paired (baseline and post-baseline, all of which were at Week 24 or later) genotypically identical
isolates. Twelve of the 19 had a post-baseline ≥4-fold increase in bedaquiline MIC. Whole genome
sequencing of 9 of these 12 post-baseline isolates was done and no mutations were found in the ATP
synthase operon. All 9 were found to have a mutation in Rv0678. Eleven of the twelve (11/12) increases
in bedaquiline MIC were seen in patients with pre-XDR-TB or with XDR-TB. Pre-XDR-TB is defined
as MDR-TB isolates resistant to either a fluoroquinolone or a second line injectable drug, and XDRTB
as MDR-TB isolates resistant to both a fluoroquinolone and a second line injectable drug. Based on
available data, response rate (culture conversion at week 120 endpoint) was similar in subjects with ≥4-
fold increases in bedaquiline MIC (5/12) and subjects with < 4-fold increases (3/7).
Susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy
and precision of testing. Assays using standard bedaquiline powder should provide the following range
of MIC values shown in Table 3.
Table 3: Quality Control Ranges using Agar and Broth Dilution Methods
and M.tuberculos is H37Rv
||Bedaquiline MIC (micrograms /mL)
|M. tuberculosis H37Rv
||0.015 – 0.06
||0.015 – 0.12
||0.015 – 0.12
Animal Toxicology And/Or Pharmacology
Bedaquiline is a cationic, amphiphilic drug that induced phospholipidosis (at almost all doses, even
after very short exposures) in drug-treated animals, mainly in cells of the monocytic phagocytic system
(MPS). All species tested showed drug-related increases in pigment-laden and/or foamy macrophages,
mostly in the lymph nodes, spleen, lungs, liver, stomach, skeletal muscle, pancreas and/or uterus. After
treatment ended, these findings were slowly reversible. Muscle degeneration was observed in several
species at the highest doses tested. For example the diaphragm, esophagus, quadriceps and tongue of
rats were affected after 26 weeks of treatment at doses similar to clinical exposures based on AUC
comparisons. These findings were not seen after a 12-week, treatment-free, recovery period and were
not present in rats given the same dose biweekly. Degeneration of the fundic mucosa of the stomach,
hepatocellular hypertrophy and pancreatitis were also seen.
A placebo-controlled, double-blind, randomized trial (Study 1) was conducted in patients with newly
diagnosed sputum smear-positive MDR pulmonary M. tuberculosis. All patients received a combination
of five other antimycobacterial drugs used to treat MDR-TB (i.e., ethionamide, kanamycin,
pyrazinamide, ofloxacin, and cycloserine/terizidone or available alternative) for a total duration of 18–
24 months or at least 12 months after the first confirmed negative culture. In addition to this regimen,
patients were randomized to receive 24 weeks of treatment with SIRTURO 400 mg once daily for the
first 2 weeks followed by 200 mg 3 times per week for 22 weeks or matching placebo for the same
duration. Overall, 79 patients were radomized to the SIRTURO arm and 81 to the placebo arm. A final
evaluation was conducted at Week 120.
Sixty-seven patients randomized to SIRTURO and 66 patients randomized to placebo had confirmed
MDR-TB, based on susceptibility tests (taken prior to randomization) or medical history if no
susceptibility results were available, and were included in the efficacy analyses. Demographics were
as follows: 63% of the study population was male, with a median age of 34 years, 35% were Black, and
15% were HIV-positive (median CD4 cell count 468 cells/μL). Most patients had cavitation in one lung
(62%); and 18% of patients had cavitation in both lungs.
Time to sputum culture conversion was defined as the interval in days between the first dose of study
drug and the date of the first of two consecutive negative sputum cultures collected at least 25 days
apart during treatment. In this trial, the SIRTURO treatment group had a decreased time to culture
conversion and improved culture conversion rates compared to the placebo treatment group at Week 24.
Median time to culture conversion was 83 days for the SIRTURO treatment group compared to 125 days
for the placebo treatment group. Table 4 shows the proportion of patients with sputum culture
conversion at Week 24 and Week 120.
Table 4: Culture Conversion Status in Patients with MDR-TB at Week 24
and Week 120 in Study 1
weeks ) +
weeks ) +
| Lack of
| Lack of
*A patient’s reason for treatment failure was counted only in the first row for which a
†Patients received 24 weeks of SIRTURO or placebo for the first 24 weeks and
received a combination of other antimycobacterial drugs for up to 96 weeks.
Study 2 was a smaller placebo controlled study designed similarly to Study 1 except that SIRTURO or
placebo was given for only 8 weeks instead of 24 weeks. Patients were randomized to either SIRTURO
and other drugs used to treat MDR-TB (SIRTURO treatment group) (n=23) or placebo and other drugs
used to treat MDR-TB (placebo treatment group) (n=24). Twenty-one patients randomized to the
SIRTURO treatment group and 23 patients randomized to the placebo treatment group had confirmed
MDR-TB based on subjects’ baseline M. tuberculosis isolate obtained prior to randomization. The
SIRTURO treatment group had a decreased time to culture conversion and improved culture conversion
rates compared to the placebo treatment group at Week 8. At Weeks 8 and 24, the differences in culture
conversion proportions were 38.9% (95% CI: [12.3%, 63.1%] and p-value: 0.004), 15.7% (95% CI: [-
11.9%, 41.9%] and p-value: 0.32), respectively.
Study 3 was a Phase 2b, uncontrolled study to evaluate the safety, tolerability, and efficacy of
SIRTURO as part of an individualized MDR-TB treatment regimen in 233 patients with sputum smear
positive (within 6 months prior to screening) pulmonary MDR-TB. Patients received SIRTURO for 24
weeks in combination with antibacterial drugs. Upon completion of the 24 week treatment with
SIRTURO, all patients continued to receive their background regimen in accordance with national TB
program (NTP) treatment guidelines. A final evaluation was conducted at Week 120. Treatment
responses to SIRTURO at week 120 were generally consistent with those from Study 1.
1. Clinical and Laboratory Standards Institute (CLSI). Susceptibility Testing of Mycobacteria,
Nocardiaceae, and other Aerobic Actinomycetes; Approved Standard – Second Edition. CLSI
document M24-A2. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500,
Wayne, PA, 19087, 2011.
2. Martin A, Portaels F, Palomino JC. Colorimetric redox-indicator methods for the rapid detection of
multidrug resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis. J
Antimicrob Chemother. 2007; 59 (2): 175-83.
3. Clinical and Laboratory Institute Standards (CLSI). Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard — Nineth Edition.
CLSI Document M07-A9. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite
2500, Wayne, PA, 19087, 2012.