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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 to 6-fold lower) compared to the parent compound. M2 concentrations appeared to correlate with QT prolongation.
After oral administration bedaquiline maximum plasma concentrations (Cmax) are typically achieved at approximately 5 hours post-dose. Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally up to the highest doses studied in healthy volunteers (700 mg single-dose and once daily 400 multiple doses). Administration of bedaquiline 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, bedaquiline should be taken with food to enhance its oral bioavailability.
The plasma protein binding of bedaquiline is > 99.9%. The volume of distribution in the central compartment is estimated to be approximately 164 L.
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 antimycobacterial potency. Based on preclinical studies, bedaquiline is mainly eliminated in feces. The urinary excretion of unchanged bedaquiline was < 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant. 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 peripheral tissues.
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. No dose adjustment is deemed necessary in patients with mild or moderate hepatic impairment. SIRTURO has not been studied in patients with severe hepatic impairment and should be used with caution in these patients only when the benefits outweigh the risks. Clinical monitoring for SIRTURO-related adverse reactions is recommended [see WARNINGS AND PRECAUTIONS].
SIRTURO has mainly been studied in patients with normal renal function. Renal excretion of unchanged bedaquiline is not substantial ( < 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, and no adjustment of the bedaquiline dose is needed in patients with mild or moderate renal impairment. However, in patients with severe renal impairment or end-stage renal disease requiring hemodialysis or peritoneal dialysis, bedaquiline should be used with caution and with increased monitoring for adverse effects, as 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.
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 is limited data on the use of SIRTURO in TB patients 65 years and older.
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.
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. Co-administration of bedaquiline and ketoconazole or other strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided, unless the benefit of the combination of these drugs outweighs the risk. Appropriate clinical monitoring for SIRTURO-related adverse reactions is recommended.
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)]. The combination of bedaquiline and rifamycins (e.g., rifampin, rifapentine and rifabutin) or other strong CYP3A4 inducers used systemically should be avoided.
The combination of multiple-dose bedaquiline 400 mg once daily with multiple-dose 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. No dose adjustment of isoniazid or pyrazinamide during co-administration with SIRTURO is required.
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 was observed.
Kaletra (400 mg lopinavir/100 mg ritonavir)
In a drug interaction study in healthy volunteers of single-dose bedaquiline (400 mg) and multiple-dose Kaletra 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.
Co-administration of multiple-dose nevirapine 200 mg twice daily for 4 weeks in HIV-infected patients with a single 400 mg dose of bedaquiline did not result in clinically relevant changes in the exposure to bedaquiline.
Mechanism of Action
Bedaquiline is a diarylquinoline antimycobacterial drug that inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis.
Mechanisms of resistance
Mycobacterial resistance mechanisms that affect bedaquiline include modification of the atpE target gene. Not all isolates with increased minimum inhibitory concentrations (MICs) have atpE mutations, suggesting the existence of at least one other mechanism of resistance.
Spectrum of Activity
Bedaquiline has been shown to be active against most isolates of Mycobacterium tuberculosis [see INDICATIONS AND USAGE and Clinical Studies].
Susceptibility Test Methods
In vitro susceptibility tests should be performed according to published methods1,2. Based on the available information, susceptibility test interpretive criteria for bedaquiline cannot be established at this time. When susceptibility testing is performed by the 7H10 or 7H11 agar method, a range of concentrations from 0.008 microgram per mL to 1.0 microgram per mL should be assessed. The minimum inhibitory concentration (MIC) should be determined as the lowest concentration of bedaquiline that results in growth of less than or equal to 1% of the residual subpopulation. When susceptibility testing is performed by the resazurin microtiter assay (REMA) method, a range of concentrations from 0.008 microgram per mL to 1.0 microgram per mL should be assessed. The MIC should be determined as the lowest concentration of bedaquiline that prevents a visible change of resazurin color from blue to pink. All assays should be performed in polystyrene plates or tubes. Löwenstein-Jensen (LJ) medium should not be used.
The actual MIC should be reported. A specialist in drug-resistant TB should be consulted in evaluating therapeutic options.
The bedaquiline agar (left) and REMA (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 MDRH&R-TB Isolates from Studies 1, 2, and 3
mITT Subjects: Agar Method (left) and 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. No correlation was seen between the culture conversion rates at Week 24 and baseline MICs.
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
|Baseline Bedaquiline MIC (micrograms/mL)||SIRTURO (Bedaquiline) Treatment Group 24-Week Culture Conversion Rate|
|≤ 0.008||2/2 (100)||21/25 (84.0)|
|0.015||15/18 (83.3)||33/39 (84.6)|
|0.03||40/49 (81.6)||70/92 (76.1)|
|0.06||80/105 (76.2)||45/56 (80.4)|
|0.12||35/41 (85.4)||6/7 (85.7)|
|0.25||1/2 (50.0)||3/4 (75.0)|
|0.5||4/5 (80.0)||0/1 (0)|
|≥ 1||0/1 (0)|
|N = number of subjects with data; n = number of subjects with that result; MIC = minimum inhibitory concentration; BR = background regimen|
In SIRTURO-treated patients from Studies 1, 2, and 3, with at least a four-fold increase in bedaquiline MIC from baseline and with atp operon sequencing results, no coding variation in the atp operon was seen, suggesting a mechanism of resistance other than mutations in the atpE gene. Of these subjects for the agar method, patients who experienced failure to convert their sputum or relapsed (n=9) had post-baseline isolates with 4-fold to greater than 8-fold increases in MIC (corresponding to post-baseline MICs of 0.24 to greater than 0.48 microgram/mL). For the REMA method, patients who experienced failure or relapsed had post-baseline isolates with 4-fold to greater than 16-fold increases in MIC (corresponding to post-baseline MICs of 0.015 to 1.0 microgram/mL). All 9 subjects with increased MICs and failure or relapse were infected with MDR-TB isolates that were resistant to additional antimycobacterial drugs in their treatment regimen.
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 REMA Methods and M. tuberculosis H37Rv
|Organism||Bedaquiline MIC (micrograms/mL)|
|M. tuberculosis H37Rv||0.03 - 0.12||0.03 - 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 newly diagnosed patients with multi-drug resistant pulmonary Mycobacterium tuberculosis. Patients were randomized to receive treatment with either SIRTURO and other drugs used to treat MDR-TB (SIRTURO treatment group) (n=79) or placebo plus other drugs used to treat MDR-TB (placebo treatment group) (n=81); the other drugs used to treat MDR-TB consisted of a combination of 5 other antimycobacterial drugs (ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone or available alternative). Sixty-three percent of the population was male, with a median age of 34 years, 35% were Black, and 15% were HIV-positive. Most patients had cavitation in one lung (62%); cavitation in both lungs was observed in 18% of patients.
SIRTURO was administered as 400 mg once daily for the first 2 weeks and as 200 mg 3 times per week for the following 22 weeks. After the 24-week study drug (SIRTURO or placebo) treatment phase, patients continued to receive their other drugs used to treat MDR-TB until a total treatment duration of 18 to 24 months was achieved, or at least 12 months after the first confirmed negative culture.
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 ongoing 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 after 24 weeks and 72 weeks of treatment with SIRTURO or placebo in combination with other drugs used to treat MDR-TB (with patients who discontinued or died considered as failures).
Table 4: Culture Conversion Status at Week 24 and Week
72 in Study 1
|Microbiologic Status||SIRTURO Treatment Group
N = 67
|Placebo Treatment Group
N = 66
|Difference [95% CI] p-value|
|Treatment success||52 (77.6%)||38 (57.6%)||20.0% [4.5%, 35.6%] 0.014|
|Treatment failure||15 (22.4%)||28 (42.4%)|
|Lack of conversion||5 (7.5%)||16 (24.2%)|
|Discontinuation||10 (14.9%)||12 (18.2%)|
|Treatment success||47 (70.1%)||37 (56.1%)||14.1% [-2.1%, 30.3%] 0.092|
|Treatment failure||20 (29.9%)||29 (43.9%)|
|Lack of conversion||3 (4.5%)||7 (10.6%)|
|Discontinuation||17 (25.4%)||22 (33.3%)|
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.
1. Clinical and Laboratory Standards Institute (CLSI). Susceptibility Testing of Mycobacteria, Nocardiaceae, and other Aerobic Actinomycetes; Approved Standard – 2nd ed. CLSI document M24-A2. CLSI, 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.
Last reviewed on RxList: 1/10/2013
This monograph has been modified to include the generic and brand name in many instances.
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