Bedaquiline

Bedaquiline (bedaquiline fumarate) is used to treat adult and pediatric patients with cutaneous (pulmonary) multidrug-resistant tuberculosis when conventional therapy is ineffective, especially when there is resistance to the most common first-line drugs.

Bedaquiline is an active substance from the diarylquinoline class. The therapeutic agent specifically attacks the ATP synthase of Mycobacterium tuberculosis. ATP synthase is necessary for the energy production of tuberculosis bacteria. Through this specific inhibition, bedaquiline interferes with the bacteria's ability to synthesize adenosine triphosphate (ATP). This synthesis is necessary for their energy supply. This mechanism of action leads to a bactericidal effect that occurs in both dividing and non-dividing cells of the tuberculosis bacteria. This approach distinguishes bedaquiline from other tuberculosis drugs, which often target the cell wall or DNA replication of the bacteria, and offers an effective treatment option, especially for multi-drug resistant strains.

Absorption: Maximum plasma concentrations (Cmax) of bedaquiline are reached approximately five hours after ingestion. Both Cmax and the area under the plasma concentration-time curve (AUC) increase proportionally with dose, studied up to a dose of 700 mg as a single dose and 400 mg as a daily multiple dose. The bioavailability of bedaquiline increases approximately twofold when the drug is taken with food compared to when taken on an empty stomach.

Distribution: The plasma protein binding of bedaquiline is over 99.9%, similarly for the N-monodesmethyl metabolite M2 with at least 99.8%. Animal experiments show that bedaquiline and M2 are extensively distributed to most tissues, with the exception of the brain, where uptake is low.

Metabolism (biotransformation): CYP3A4 is primarily responsible for the metabolism of bedaquiline and the formation of the active metabolite M2. Bedaquiline does not significantly inhibit or induce any of the CYP450 enzymes tested in vitro.

Elimination: The majority of the ingested dose of bedaquiline is excreted in the feces, with less than 0.001% of the dose found unchanged in the urine, indicating negligible renal clearance. After reaching Cmax, plasma concentrations of bedaquiline decline exponentially with a mean terminal elimination half-life of approximately five months for bedaquiline and M2, likely reflecting the slow clearance of the drug from peripheral tissues.

Special patient groups:

• Hepatic impairment: No dose adjustment necessary in mild to moderate impairment; not studied in severe impairment.
• Renal impairment: No significant effect of renal function on pharmacokinetic parameters; in severe impairment, exposure may be increased due to altered absorption and metabolism.
• Children and adolescents: Varying exposures based on body weight, but average exposure is similar to that in adults.
• Elderly patients: Age does not appear to affect pharmacokinetics, limited data available.
• Ethnicity: Lower exposure in patients of black skin color without clinical relevance.
• Gender: No significant differences in exposure observed between males and females.

There are only very limited data on the use of bedaquiline in pregnant women. No adverse effects on reproduction have been observed in animal experiments, but safety for humans has not been fully established. Therefore, bedaquiline should only be used during pregnancy if the expected benefit outweighs the potential risk. In general, it is recommended to avoid the use of bedaquiline during pregnancy unless there is an urgent medical need.

Lactation: Bedaquiline passes into breast milk and may reach a systemic exposure in infants similar to that in treated mothers. Studies have found that the concentration of bedaquiline in breast milk may be significantly higher than in maternal plasma, with reported milk-to-plasma ratios of up to 14:1. Plasma concentrations equivalent to those of the mother were measured in a breastfed infant. Based on these data and the unclear clinical consequences of such exposure, it is recommended that mothers on bedaquiline therapy should not breastfeed.

General information: Therapy initiation and monitoring should be performed by a physician experienced in the treatment of MDR-TB. Directly Observed Therapy (DOT) is recommended. Bedaquiline is part of an appropriate combination therapy based on WHO guidelines and susceptibility testing.

Adults (≥18 years): Week 1 to 2: 400 mg daily. Week 3 to 24: 200 mg three times a week (at least 48 hours between doses).

Children and adolescents (≥15 to <20 kg body weight):

• Week 1 to 2: 160 mg daily.
• Week 3 to 24: 80 mg three times a week.

Children and adolescents (≥20 to <30 kg body weight):

• Week 1 to 2: 200 mg daily.
• Week 3 to 24: 100 mg three times a week.

Children and adolescents (≥30 kg body weight):

• Week 1 to 2: 400 mg daily.
• Week 3 to 24: 200 mg three times a week.

Treatment duration: Standard treatment duration is 24 weeks.

In patients with extensive resistance, the duration of treatment can be extended individually, under close medical supervision.

Special patient groups:

• Elderly patients (≥65 years): Very limited clinical data available.
• Hepatic impairment:
  • Mild to moderate: No dose adjustment required.
  • Severe: Use not recommended as no data available.
• Renal impairment:
  • Mild to moderate: No dose adjustment required.
  • Severe or terminal renal insufficiency: Cautious use recommended.
• Children under 5 years or <15 kg: Safety and efficacy not established.

Common side effects that may occur during bedaquiline therapy include:

• Headache
• dizziness
• Prolonged QT interval
• nausea
• vomiting
• Diarrhea
• Elevated transaminases
• Arthralgia
• myalgia

The following interactions should be considered when using bedaquiline:

• CYP3A4 inducers: Concomitant use of bedaquiline with strong or moderate CYP3A4 inducers such as rifampicin, rifapentine, efavirenz, carbamazepine and phenytoin may reduce the efficacy of bedaquiline by significantly reducing its bioavailability. For example, rifampicin reduced bioavailability by 52%.
• CYP3A4 inhibitors: Potent CYP3A4 inhibitors such as ketoconazole may increase the bioavailability of bedaquiline. Short-term co-administration of bedaquiline and ketoconazole increased bedaquiline bioavailability by 22%. Prolonged concomitant use with strong CYP3A4 inhibitors could lead to an even greater increase and should therefore be avoided or treated with caution.
• Other tuberculosis drugs: Short-term concomitant use of bedaquiline with isoniazid and pyrazinamide did not significantly alter the bioavailability of these drugs, so no dose adjustment is required. The combination with ethambutol, kanamycin, ofloxacin and cycloserine also showed no significant pharmacokinetic interactions in studies with MDR-TB patients.
• Antiretroviral drugs: The concomitant use of bedaquiline with lopinavir/ritonavir may increase the bioavailability of bedaquiline by approximately 22%, which could further increase with prolonged use. The concomitant use of bedaquiline with other HIV protease inhibitors containing ritonavir also increases bedaquiline bioavailability. It has also been observed that bedaquiline in combination with nevirapine does not cause significant changes in bioavailability.
• QT interval-prolonging drugs: Combinations of bedaquiline with other drugs that prolong the QT interval (such as ketoconazole and clofazimine) may have an additive or synergistic effect and increase QT prolongation. This requires regular ECG monitoring, especially in combination with clofazimine, where significant prolongations have been observed.

Hypersensitivity to the active substance

Restrictions on use:

• No data for the treatment of extrapulmonary TB, infections caused by mycobacteria other than Mycobacterium tuberculosis, or latent TB infections. Bedaquiline should not be used for the treatment of TB caused by drug-susceptible Mycobacterium tuberculosis.

Resistance: Bedaquiline should only be used in combination therapy recommended by WHO guidelines for the treatment of MDR-TB to prevent the development of resistance.

Mortality: In one study, more deaths occurred in the bedaquiline group than in the placebo group. The reason for this is unclear and a direct link with bedaquiline is not certain.

Cardiovascular safety: Since bedaquiline may prolong the QTc interval, regular ECG monitoring is required. Electrolyte disturbances should be corrected before and during treatment. Caution should be exercised when combining bedaquiline with other QT interval-prolonging medicinal products.

Hepatic safety: Increases in liver enzymes have been observed. Liver function should be monitored regularly and if significant elevations occur, bedaquiline and/or other hepatotoxic drugs should be discontinued.

Alcohol and other hepatotoxic substances should be avoided during treatment.

Special patient groups:

• Bedaquiline should be used with caution in patients over 65 years of age, patients with heart failure, pre-existing hypothyroidism, bradyarrhythmia, or a history of torsade de pointes tachycardia. Its use is not recommended in patients with a QTcF interval > 450 ms or with existing hypokalemia.
• Adolescents weighing between 30 and 40 kg are expected to have a higher average exposure compared to adult patients, which may be associated with an increased risk of QT prolongation or hepatotoxicity.

Alternatives: Alternatives to bedaquiline include other drugs as 2nd-line agents for the treatment of multidrug-resistant tuberculosis:

• dapsone
• other aminoglycosides such as kanamycin and capreomycin
• moxifloxacin and linezolid
• Meropenem with clavulanic acid
• delamanid
• bedaquiline
• prothionamide
• terizidone

1. Singh B et al. (2023) Bedaquiline in Drug-Resistant Tuberculosis: A Mini-Review. Curr Mol Pharmacol 16:243-253.
2. Yu Y et al. (2025) Real-world effectiveness and safety of prolonged bedaquiline course in the treatment of drug-resistant tuberculosis-a multi-center retrospective cohort study in a country with a high burden of drug-resistant tuberculosis. Microbiol Spectr 13:e0009725.