Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340, Beerse, Belgium
Pharmacotherapeutic group: Antimycobacterials, drugs for treatment of tuberculosis
ATC code: J04AK05
Bedaquiline is a diarylquinoline. Bedaquiline specifically inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, an essential enzyme for the generation of energy in Mycobacterium tuberculosis. The inhibition of ATP synthase leads to bactericidal effects for both replicating and non-replicating tubercle bacilli.
Bedaquiline has activity against M. tuberculosis complex strains with a minimal inhibitory concentration (MIC) in the range of ≤0.008 to 0.25 mg/L. The N-monodesmethyl metabolite (M2) is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (3- to 6-fold lower) compared to the parent compound.
The intracellular bactericidal activity of bedaquiline in primary peritoneal macrophages and in a macrophage-like cell line was greater than its extracellular activity. Bedaquiline is also bactericidal against dormant (non-replicating) tubercle bacilli. In the mouse model for TB infection, bedaquiline has demonstrated bactericidal and sterilizing activities.
Bedaquiline is bacteriostatic for many non-tuberculous mycobacterial species. Mycobacterium xenopi, Mycobacterium novocastrense, Mycobacterium shimoidei, Mycobacterium flavescens and non-mycobacterial species are considered inherently resistant to bedaquiline.
Within the concentration range achieved with the therapeutic dose, no pharmacokinetic/pharmacodynamic relationship was observed in patients.
Acquired resistance mechanisms that affect bedaquiline MICs include mutations in the atpE gene, which codes for the ATP synthase target, and in the Rv0678 gene, which regulates the expression of the MmpS5-MmpL5 efflux pump. 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 mg/L. 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 0.5 mg/L. The majority of isolates that are phenotypically resistant to bedaquiline are cross-resistant to clofazimine. Isolates that are resistant to clofazimine can still be susceptible to bedaquiline.
The impact of high baseline bedaquiline MICs, the presence of Rv0678 based mutations at baseline, and/or increased post-baseline bedaquiline MICs on microbiological outcomes is unclear because of the low incidence of such cases in clinical trials.
MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for bedaquiline and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory- concentration-mic-breakpoints_en.xlsx
Commonly susceptible species:
Mycobacterium tuberculosis
Inherently resistant organisms:
Mycobacterium xenopi
Mycobacterium novocastrense
Mycobacterium shimoidei
Mycobacterium flavescens
Non-mycobacterial species
A Phase IIb, placebo-controlled, double-blind, randomised trial (C208) evaluated the antibacterial activity, safety, and tolerability of SIRTURO in newly diagnosed adult patients with sputum smear-positive pulmonary TB due to M. tuberculosis resistant to at least rifampicin and isoniazid, including patients with resistance to second-line injectables or fluoroquinolones. Patients received SIRTURO (N=79) or placebo (N=81) for 24 weeks, both in combination with a preferred 5-drug background regimen (BR) consisting of ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone. SIRTURO was administered as 400 mg once daily for the first 2 weeks and as 200 mg 3 times/week for the following 22 weeks. After the 24-week investigational period, the background regimen was continued to complete 18 to 24 months of total treatment. A final evaluation was conducted at Week 120. Main demographics for the ITT population were as follows: 63.1% were males, median age 34 years, 35% were Black, and 15% were HIV-positive. Cavitation in one lung was seen in 58% of patients, and in both lungs in 16%. For patients in the mITT population with full characterisation of resistance status, 76% (85/112) were infected with a M. tuberculosis strain resistant to rifampicin and isoniazid and 24% (27/112) with a M. tuberculosis strain also resistant to second-line injectables or fluoroquinolones.
The primary outcome parameter was the time to sputum culture conversion (i.e., the interval between the first SIRTURO intake and the first of two consecutive negative mycobacteria growth indicator tube (MGIT) cultures from sputum collected at least 25 days apart) during treatment with SIRTURO or placebo (median time to conversion was 83 days for the SIRTURO group, 125 days for the placebo group (hazard ratio, 95% CI: 2.44 [1.57; 3.80]), p<0.0001).
In the SIRTURO group, no or only minor differences in time to culture conversion and culture conversion rates were observed between patients with a M. tuberculosis strain resistant to rifampicin and isoniazid and patients with a M. tuberculosis strain also resistant to second-line injectables or fluoroquinolones.
Response rates at Week 24 and Week 120 (i.e., approximately 6 months after stopping all therapy) are presented in Table 3.
Table 3. Culture Conversion Status in C208:
| Culture Conversion Status, n (%) | mITT Population | |||
|---|---|---|---|---|
| N | SIRTURO/BR | N | Placebo/BR | |
| Overall responder at Week 24 | 66 | 52 (78.8%) | 66 | 38 (57.6%) |
| Patients with a M. tuberculosis strain resistant to rifampicin and isoniazid | 39 | 32 (82.1%) | 45 | 28 (62.2%) |
| Patients with a M. tuberculosis strain resistant to rifampicin and isoniazid, and also to second-line injectables or fluoroquinolones | 15 | 11 (73.3%) | 12 | 4 (33.3%) |
| Overall non-respondera at Week 24 | 66 | 14 (21.2%) | 66 | 28 (42.4%) |
| Overall responder at Week 120 | 66 | 41 (62.1%) | 66 | 29 (43.9%) |
| Patients with a M. tuberculosis strain resistant to rifampicin and isoniazid | 39b | 27 (69.2%) | 46b,c | 20 (43.5%) |
| Patients infected with a M. tuberculosis strain resistant to rifampicin and isoniazid, and also to second-line injectables or fluoroquinolones | 15b | 9 (60.0%) | 12b | 5 (41.7%) |
| Overall non-respondera at Week 120 | 66 | 25 (37.9%) | 66 | 37 (56.1%) |
| Failure to convert | 66 | 8 (12.1%) | 66 | 15 (22.7%) |
| Relapsed | 66 | 6 (9.1%) | 66 | 10 (15.2%) |
| Discontinued but converted | 66 | 11 (16.7%) | 66 | 12 (18.2%) |
a Patients who died during the trial or discontinued the trial were considered as non-responders.
b Extent of resistance based on central laboratory drug susceptibility testing results was not available for 20 patients in the mITT population (12 in the SIRTURO group and 8 in the placebo group). These patients were excluded from the subgroup analysis by extent of resistance of M. tuberculosis strain.
c Central laboratory drug susceptibility testing results became available for one additional placebo patient after the Week 24 interim analysis.
d Relapse was defined in the trial as having a positive sputum culture after or during treatment following prior sputum culture conversion.
During the trial, 12.7% (10/79) of the patients died in the SIRTURO treatment group (N=79) compared to 3.7% (3/81) of the patients in the placebo group (N=81). One death occurred during administration of SIRTURO. The median time to death for the remaining nine patients was 344 days after last intake of SIRTURO. In the SIRTURO treatment group, the most common cause of death as reported by the investigator was TB (5 patients). The causes of death in the remaining patients treated with SIRTURO varied. During the trial, there was no evidence of antecedent significant QTcF prolongation or clinically significant dysrhythmia in any of the patients who died.
Study C209 evaluated the safety, tolerability, and efficacy of 24 weeks treatment with open-label SIRTURO as part of an individualised treatment regimen in 233 adult patients who were sputum smear positive within 6 months prior to screening. This study included patients with M. tuberculosis strains of all three resistance categories (resistant to rifampicin and isoniazid, also resistant to second-line injectables or fluoroquinolones, and also resistant to second-line injectables and fluoroquinolones).
The primary efficacy endpoint was the time to sputum culture conversion during treatment with SIRTURO (median 57 days, for 205 patients with sufficient data). At Week 24, sputum culture conversion was seen in 163/205 (79.5%) patients. Conversion rates at Week 24 were highest (87.1%; 81/93) in patients with M. tuberculosis isolates resistant to only rifampicin and isoniazid, 77.3% (34/44) in patients with pulmonary TB due to M. tuberculosis resistant to rifampicin, isoniazid, second-line injectables or fluoroquinolones, and lowest (54.1%; 20/37) in patients with M. tuberculosis isolates resistant to rifampicin, isoniazid, second-line injectables and fluoroquinolones. Extent of resistance based on central laboratory drug susceptibility testing results was not available for 31 patients in the mITT population. These patients were excluded from the subgroup analysis by extent of resistance of M. tuberculosis strain.
At Week 120, sputum culture conversion was seen in 148/205 (72.2%) patients. Conversion rates at Week 120 were highest (73.1%; 68/93) in patients with M. tuberculosis isolates resistant to only rifampicin and isoniazid, 70.5% (31/44) in patients with pulmonary TB due to M. tuberculosis resistant to rifampicin, isoniazid, second-line injectables or fluoroquinolones and lowest (62.2%; 23/37) in patients with M. tuberculosis isolates resistant to rifampicin, isoniazid, second-line injectables and fluoroquinolones.
At both Week 24 and Week 120, responder rates were higher for patients on 3 or more active substances (in vitro) in their background regimen.
In the open-label C209 trial, 6.9% (16/233) of the patients died. The most common cause of death as reported by the investigator was TB (9 patients). Eight of nine patients who died of TB had not converted or had relapsed. The causes of death in the remaining patients varied.
STREAM Stage 2 was a Phase III, open-label, multicentre, active-controlled, randomised trial conducted to evaluate the efficacy and safety of SIRTURO co-administered with other oral anti-TB drugs for 40 weeks in patients with sputum smear-positive pulmonary TB caused by M. tuberculosis that was resistant to at least rifampicin, with or without resistance additionally to isoniazid and/or second-line injectable agents or fluoroquinolones (but not both).
Patients were randomised to one of four treatment groups:
SIRTURO was administered as 400 mg once daily for the first 2 weeks and 200 mg 3 times/week for the following 38 weeks (in Group C) or 26 weeks (in Group D). Changes in treatment regimen were permitted at the discretion of the investigator in all groups. Enrolment in Groups A and D was stopped prematurely due to changes in the standard of care for TB treatment.
The primary objective was to assess whether the proportion of patients with a favourable efficacy outcome in Group C was noninferior to that in Group B at Week 76.
The primary efficacy outcome measure was the proportion of patients with a favourable outcome at Week 76. A favourable outcome at Week 76 was defined as last 2 consecutive cultures negative and no unfavourable outcome. An unfavourable outcome at Week 76 encompassed clinically relevant changes in treatment, all-cause mortality, at least 1 of the last 2 culture results positive, or no culture results within the Week 76 window.
In the overall study population (N=588), 59.9% were male, median age was 32.7 years, 47.3% were Asian, 36.6% were Black, 16.2% were White and 16.5% were HIV-coinfected. Most patients had cavitation (73.1%), with multiple cavities in 55.3% of patients. Of the 543 patients in the primary efficacy population (mITT population, defined as patients with a positive culture for M. tuberculosis at screening or randomisation), 12.5% of the patient's M. tuberculosis isolates were resistant to rifampicin while susceptible to isoniazid, 76.4% had resistance to at least rifampicin and isoniazid, and 11% had resistance to rifampicin, isoniazid and either second-line injectables or fluoroquinolones.
Table 4 shows the proportion of patients with a favourable or unfavourable outcome at Week 76 in the STREAM Stage 2 Phase III trial. The proportion of participants with a favourable outcome at Week 76 was 82.7% in Group C compared to 71.1% in Group B. The main reason for an unfavourable outcome in both groups was extension or modification of the assigned treatment regimen. Limitations of the study included its open-label design; changes to the allocated treatment regimens were permitted in case of treatment failure, recurrence or serious toxicity.
Table 4. Primary Analysis in STREAM Stage 2 (Phase III Trial):
| mITT Population | ||
|---|---|---|
| SIRTUROa (N=196) | Active Controlb (N=187) | |
| Favourable outcome at Week 76 n (%) | 162 (82.7) | 133 (71.1) |
| Unfavourable outcome at Week 76 n (%) | 34 (17.3) | 54 (28.9) |
| Reasons for unfavourable outcome through Week 76c | ||
| Treatment modified or extended | 16 (8.2) | 43 (23.0) |
| No culture results within Week 76 window | 12 (6.1%) | 7 (3.7) |
| Death through Week 76 | 5 (2.6) | 2 (1.1) |
| At least one of last 2 cultures positive at Week 76 | 1 (0.5) | 2 (1.1) |
mITT = modified intent-to-treat
a Group C 40-week, all-oral regimen of SIRTURO, levofloxacin, clofazimine, ethambutol, and pyrazinamide, supplemented by high-dose isoniazid and prothionamide in the first 16 weeks (intensive phase).
b Group B 40-week control treatment of moxifloxacin or levofloxacin, clofazimine, ethambutol, pyrazinamide, supplemented by injectable kanamycin, high dose isoniazid and prothionamide in the first 16 weeks (intensive phase).
c Patients were classified by the first event that made the patient unfavourable. Of the patients with an unfavourable outcome at Week 76 in the control group, 29 patients had a treatment modification from their allocated treatment that included SIRTURO as part of a salvage regimen.
The frequency of deaths was similar across treatment groups through Week 132. In the 40-week SIRTURO group, 11/211 (5.2%) patients died; the most common cause of death was related to TB (5 patients). In the 40-week active control group, 8/202 (4.0%) patients died, including 4 of 29 patients who received SIRTURO as part of a salvage treatment; the most common cause of death was related to respiratory pathology. The adjusted difference in proportion of fatal adverse events between the 40-week SIRTURO group and the 40-week active control group was 1.2% [95% CI (-2.8%; 5.2%)].
The pharmacokinetics, safety and tolerability of SIRTURO in combination with a background regimen were evaluated in trial C211, a single-arm, open-label, multi-cohort Phase II trial in 45 patients with confirmed or probable pulmonary TB due to M. tuberculosis resistant to at least rifampicin.
Fifteen patients had a median age of 16 years (range: 14 to 17 years), weighed 38 to 75 kg, and were 80% female, 53% Black, 33% White and 13% Asian. The patients were to complete at least 24 weeks of treatment with SIRTURO administered as 400 mg once daily for the first 2 weeks and 200 mg 3 times/week for the following 22 weeks using 100 mg tablets.
In the subset of patients with MGIT culture positive pulmonary TB at baseline, treatment with a regimen including SIRTURO resulted in conversion to a negative culture in 87.5% (7/8 MGIT culture evaluable patients) at Week 24, which was sustained at Week 120.
Fifteen patients had a median age of 7 years (range: 5 to 10 years), weighed 14 to 36 kg, and were 60% female, 60% Black, 33% White and 7% Asian. The patients were to complete at least 24 weeks of treatment with SIRTURO administered as 200 mg once daily for the first 2 weeks and 100 mg 3 times/week for the following 22 weeks using 20 mg tablets.
In the subset of patients with MGIT culture positive pulmonary TB at baseline, treatment with a regimen including SIRTURO resulted in conversion to a negative culture in 100% (3/3 MGIT culture evaluable patients) at Week 24, which was sustained at Week 120.
Fifteen patients had a median age of 3.8 years (range: 2.0 to 4.9 years), weighed 10 to 16 kg, and were 47% female, 27% Black and 73% Asian. The patients were to complete at least 24 weeks of treatment with SIRTURO administered as 80 to 120 mg once daily for the first 2 weeks and 40 to 60 mg 3 times/week for the following 22 weeks based on weight, using 20 mg tablets.
In the one patient with MGIT culture positive pulmonary TB at baseline, treatment with a regimen including SIRTURO resulted in conversion to a negative culture (1/1 MGIT culture evaluable patients) at Week 24, which was sustained at Week 120.
The European Medicines Agency has deferred the obligation to submit the results of studies with SIRTURO in one or more subsets of the paediatric population in the treatment of M. tuberculosis resistant to at least rifampicin and isoniazid (see section 4.2 for information on paediatric use).
The pharmacokinetic properties of bedaquiline have been evaluated in healthy adults and in patients 2 years of age and older with active TB. Exposure to bedaquiline was lower in patients with pulmonary TB due to M. tuberculosis resistant to at least rifampicin and isoniazid than in healthy adults.
In adult patients with pulmonary TB, following 2 weeks of 400 mg bedaquiline once daily, mean (SD) Cmax and AUC24h, ng∙h/mL were 3060 (1124) ng/mL and 41510 (15064) ng∙h/mL, respectively, for bedaquiline and 326 (135) ng/mL and 7267 (3029) ng∙h/mL, respectively, for the M2 metabolite. Following 38 weeks of 200 mg bedaquiline three times weekly, mean (SD) Cmax and AUC168h, ng∙h/mL were 1787 (666) ng/mL and 168376 (74476) ng∙h/mL, respectively, for bedaquiline and 246 (103) ng/mL and 39540 (17220) ng∙h/mL, respectively, for the M2 metabolite.
Maximum plasma concentrations (Cmax) are typically achieved at about 5 hours post-dose. Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally up to 700 mg single-dose and once daily 400 mg for 14 days. Administration of bedaquiline with food 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% in all species tested, including humans. The plasma protein binding of its active metabolite, M2, in humans is at least 99.8%. In animals, bedaquiline and M2 are extensively distributed to most tissues, however, brain uptake is low.
CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation and metabolism of M2.
In vitro, bedaquiline does not significantly inhibit the activity of any of the CYP450 enzymes tested (CYP1A2, CYP2A6, CYP2C8/9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A4/5 and CYP4A) and does not induce CYP1A2, CYP2C9 or CYP2C19 activities.
Bedaquiline and M2 were not substrates of P-gp in vitro. Bedaquiline was a weak OCT1, OATP1B1 and OATP1B3 substrate in vitro, while M2 was not. Bedaquiline was not a substrate of MRP2 and BCRP in vitro. Bedaquiline and M2 did not inhibit the transporters P-gp, OATP1B1, OATP1B3, BCRP, OAT1, OAT3, OCT1, OCT2, MATE1 and MATE2 at clinically relevant concentrations in vitro. An in vitro study indicated a potential for bedaquiline to inhibit BCRP at the concentrations achieved in the intestine after oral administration. The clinical relevance is unknown.
Based on the preclinical studies, the bulk of the administered dose is eliminated in faeces. The urinary excretion of unchanged bedaquiline was <0.001% of the dose in clinical studies, indicating that renal clearance of unchanged active substance is insignificant. After reaching Cmax, bedaquiline concentrations decline tri-exponentially. The mean terminal elimination half-life of both bedaquiline and M2 is about 5 months (ranging from 2 to 8 months). This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from peripheral tissues.
A single-dose study of SIRTURO in 8 participants with moderate hepatic impairment (Child-Pugh B) demonstrated exposure to bedaquiline and M2 (AUC672h) was 19% lower compared to healthy participants. No dose adjustment is deemed necessary in patients with mild or moderate hepatic impairment. Bedaquiline has not been studied in patients with severe hepatic impairment (see section 4.2).
SIRTURO has mainly been studied in patients with normal renal function. Renal excretion of unchanged bedaquiline is insignificant (<0.001%).
In a population pharmacokinetic analysis of tuberculosis patients treated with SIRTURO 200 mg three times a week, creatinine clearance (range: 40 to 227 mL/min) 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 (creatinine clearance <30 mL/min) or end-stage renal disease requiring haemodialysis or peritoneal dialysis, bedaquiline concentrations may be increased due to alteration of active substance 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 haemodialysis or peritoneal dialysis.
In paediatric patients aged 2 years to less than 18 years, the expected average (90% prediction interval) plasma exposure of bedaquiline (AUC168h) at Week 24 when treated with the recommended dosing regimen based on weight is:
The average plasma exposure of bedaquiline (AUC168h) at Week 24 in adults was predicted to be 127 μg∙h/mL (90% prediction interval: 39.7 to 249 μg∙h/mL).
The pharmacokinetics of SIRTURO in paediatric patients less than 2 years of age or weighing less than 7 kg have not been established.
In a population pharmacokinetic analysis of tuberculosis patients treated with SIRTURO, age was not found to influence the pharmacokinetics of bedaquiline.
In five patients 65 to 69 years of age, the systemic bedaquiline exposure was similar to that of other adults.
In a population pharmacokinetic analysis of tuberculosis patients treated with SIRTURO, exposure to bedaquiline was found to be lower in Black patients than in patients from other race categories. This lower bedaquiline exposure in Black patients was not associated with lower efficacy in clinical trials, and no dose adjustment is needed.
In a population pharmacokinetic analysis of tuberculosis patients treated with SIRTURO, no clinically relevant differences in exposure between men and women were observed.
Animal toxicology studies have been conducted with bedaquiline administration up to 3 months in mice, up to 6 months in rats, and up to 9 months in dogs. The plasma bedaquiline exposure (AUC) in rats and dogs was similar to that observed in humans. Bedaquiline was associated with effects in target organs which included monocytic phagocytic system (MPS), skeletal muscle, liver, stomach, pancreas and heart muscle. All of these toxicities except effects on MPS were monitored clinically. In the MPS of all species, pigment-laden and/or foamy macrophages were also seen in various tissues, consistent with phospholipidosis. The significance of phospholipidosis in humans is unknown. Most of the observed changes occurred after prolonged daily dosing and subsequent increases in plasma and tissue concentrations of the active substance. After treatment cessation, all indications of toxicity exhibited at least partial recovery to good recovery.
In a rat carcinogenicity study, bedaquiline, at the high doses of 20 mg/kg/day in males and 10 mg/kg/day in females, did not induce any treatment-related increases in tumour incidences. Compared to the exposures (AUC) observed in patients with pulmonary TB in the bedaquiline Phase II trials, the exposures (AUC) in rats at high doses were similar in males and 2-fold higher in females for bedaquiline, and 3-fold higher in males and 2-fold higher in females for M2.
In vitro and in vivo genotoxicity tests indicated that bedaquiline did not have any mutagenic or clastogenic effects.
Bedaquiline had no effects on fertility when evaluated in female rats. Three of 24 male rats treated with high bedaquiline doses failed to produce offspring in the fertility study. Normal spermatogenesis and a normal amount of spermatozoa in the epididymides were noted in these animals. No structural abnormalities in the testes and epididymides were seen after up to 6-months of bedaquiline treatment. No relevant bedaquiline-related effects on developmental toxicity parameters were observed in rats and rabbits. The corresponding plasma exposure (AUC) was 2-fold higher in rats compared to humans. In the rat, no adverse effects were observed in a pre- and post-natal development study at maternal plasma exposure (AUC) similar to humans and exposure in the offspring 3-fold higher than in adult humans. There was no effect of maternal treatment with bedaquiline at any dose level on sexual maturation, behavioural development, mating performance, fertility or reproductive capacity of the F1 generation animals. Body weight decreases in pups were noted in high dose groups during the lactation period after exposure to bedaquiline via milk and were not a consequence of in utero exposure. Concentrations of bedaquiline in milk were 6- to12-fold higher than the maximum concentration observed in maternal plasma.
In a juvenile rat toxicity study, the no observed adverse effect level (NOAEL) was 15 mg/kg/day (maximum dose 45 mg/kg/day) for observations of diffuse inflammation and/or degeneration in skeletal muscle (reversible), oesophagus (reversible) and tongue (reversible), liver hypertrophy (reversible) and corticomedullary renal mineralisation (partial recovery in males, and no recovery in females within 8 weeks after end of exposure). The NOAEL corresponds to a plasma AUC24h of 13.1 and 35.6 μg∙h/mL for bedaquiline (~0.7x clinical dose) and 10.5 and 16.3 μg∙h/mL for the N-monodesmethyl metabolite of bedaquiline (M2) in males and females (~1.8x clinical dose), respectively.
Environmental risk assessment studies have shown that bedaquiline has the potential to be persistent, bioaccumulative and toxic to the environment (see section 6.6).
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