Pharmacology: Mechanism of Action:
Bedaquiline is a diarylquinoline antimycobacterial drug (see Microbiology in the following section).
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 Precautions.)
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 randomized 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 1 shows the proportion of patients with sputum culture conversion at Week 24 and Week 120. (See Table 1.)
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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.
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 & 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 antimycobacterial potency.
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.
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.
Hepatic Impairment: 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 Precautions.)
Renal Impairment: 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 Precautions).
Sex: In a population pharmacokinetic analysis of MDR-TB patients treated with SIRTURO no clinically relevant difference in exposure between men and women were observed.
Race/Ethnicity: 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.
HIV Co-infection: There are limited data on the use of SIRTURO in HIV co infected patients (see Interactions).
Geriatric Population: There are limited data on the use of SIRTURO in tuberculosis 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.
Pediatric Population: The pharmacokinetics of SIRTURO in pediatric patients have not been evaluated.
Drug-Drug Interactions: 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.
Ketoconazole: 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
of bedaquiline by 22% [90% CI (12; 32)], 9% [90% CI (-2, 21)] and 33% [90% CI (24, 43)] respectively (see Interactions).
Rifampin: 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 Interactions).
Antimicrobial agents: 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 (see 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 was observed.
Lopinavir/ritonavir: 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 Interactions).
Nevirapine: 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 (see Interactions).
Efavirenz: 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 Interactions).
Toxicology: Carcinogenesis, Mutagenesis, and Impairment of Fertility:
Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. Exposures at this dose in rats (AUCs) were within 1 fold to 2 fold of those observed in subjects in the Phase 2 clinical trials.
No mutagenic or clastogenic effects were detected in the in vitro
non-mammalian reverse mutation (Ames) test, in vitro
mammalian (mouse lymphoma) forward mutation assay and an in vivo
mouse bone marrow micronucleus assay.
SIRTURO had no effects on fertility when evaluated in male and female rats. No relevant drug related effects on developmental toxicity parameters were observed in rats and rabbits. The corresponding plasma exposure (AUC) was 2 fold higher in rats and lower for rabbits compared to humans. There was no effect of maternal treatment with bedaquiline at any dose level on sexual maturation, behavioral 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-fold to 12-fold higher that the maximum concentration observed in maternal plasma.
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.
Microbiology: 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.
Cross-Resistance: 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 clofazimine.
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 & Clinical Studies in the previous text).
Susceptibility Test Methods: In vitro
susceptibility tests should be performed according to published methods 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. (See Figure and Table 2.)
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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 3 below. Based on the available data, there was no trend for poor microbiologic outcomes related to baseline bedaquiline MIC. (See Table 2.)
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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 XDR-TB 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. (See Table 3.)
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