Bedaquiline - Indications, Doses, Toxicities, and Mechanism of Action

Overview

Bedaquiline is a quinoline-based antitubercular drug and a potent antimycobacterial agent. The US Food and Drug Administration (FDA) approved the accelerated use of Bedaquiline to treat multidrug-resistant tuberculosis on 28 December 2012. It is a diarylquinoline compound, which is a member of quinolines. It is a member of naphthalenes and an organobromine compound.

Bedaquiline has the chemical structure of aromatic ether with a tertiary alcohol and a tertiary amino group. It is added along with antituberculosis drug regimes in combination therapy because it enhances the antimycobacterial activity of second-line antitubercular drugs. Bedaquiline became the first new antitubercular drug to treat multidrug-resistant tuberculosis, exhibiting a novel mechanism of drug action, to be approved in 40 years since Rifampicin's approval in 1974.

What Are the Indications of Bedaquiline?

Strict guidelines are formulated and published for the use of Bedaquiline. The commonly approved indications for using Bedaquiline are as follows -

• For treating multidrug-resistant tuberculosis (MDR-TB).

• Pulmonary multidrug-resistant tuberculosis.

• Active multidrug-resistant tuberculosis disease.

• To treat adult patients (above 18 years) and adolescent individuals (12 to 18 years) in whom the presence of multi-drug resistant tuberculosis is confirmed.

• Its use is indicated only when the drug susceptibility of the causative strain is known and identified.

• Bedaquline is highly indicated only when an already existing anti-tuberculosis treatment regimen has failed and cannot be continued effectively.

Contraindications

Use of Bedaquline is strictly contraindicated in the following conditions.

• Latent infections caused by Mycobacterium tuberculosis.

• Drug-sensitive tuberculosis that responds to first-line antitubercular drugs.

• Extra-pulmonary tuberculosis.

• Infections that are caused due to non-tuberculous Mycobacteria.

• HIV-infected patients with MDR-TB secondary infection since its safety and efficacy are not yet clinically proven.

• Mycobacterial infections caused by Mycobacterium tuberculosis, whose drug susceptibility is still not identified.

Dose Strengths and Available Forms

• Bedaquiline is available in 100 mg tablets.

• It is uncoated (no film or capsule covering) and white.

• The tablets are round and biconvex in shape.

Dosage and Route of Administration

• Bedaquiline tablets are administered by oral route.

• The mode of administration is direct observational therapy (DOT).

Recommended Dose

The currently established guidelines for the safety and efficacy of Bedaquiline have restricted its use to only 24 weeks. The recommended therapeutic dose of Bedaquiline for treating multidrug-resistant tuberculosis is as follows -

• For the First Two Weeks - 400 milligrams (four tablets of 100 grams) are given once daily.

• Following Next 22 Weeks (3rd Week - 24th Week) - 200 mg (two tablets of 100 milligrams) three times in a single week (total dosage = 600 milligrams per week).

Recommended Population

• Adult Patients - individuals 18 years of age and above.

• Pediatric Patients - adolescents 12 to 18 years old and above 30 kg in body weight.

What Is Direct Observational Therapy?

In direct observational therapy (DOT), an authorized healthcare provider or a designated medical professional (other than a family member) provides the prescribed antitubercular drugs. It monitors the intake by the patient (swallowing each dose) under direct supervision.

The benefits of DOT therapy are as follows -

• It ensures that the affected individuals, irrespective of their social and educational backgrounds, age, and gender take the prescribed anti-TB medications correctly without missing the dosages.

• It is reported that 86 % to 90 % of patients who receive DOT therapy successfully complete the prescribed anti-TB regime compared to 61 % of those on self-administered treatment.

• Unnecessary gaps and missing dosages are avoided in DOT therapy. This prevents the spread of MDR-TB.

• DOT therapy reduces the possibility of relapse and treatment failure that usually occurs because of erratic and incomplete therapies.

• This therapy minimizes the risk of developing drug resistance by the Mycobacteria to Bedaquiline and ensures its efficacy in MDR-TB treatment.

Storage and Handling

• Bedaquiline tablets are packed and supplied in high-density polyethylene white bottles with polypropylene child-resistant closure and sealed induction liner.

• If the tablets are dispensed out of the original container, they must be stored in a light-resistant tight container with an expiration date not exceeding three months.

• It is stored at room temperature (15 to 30 degrees Celsius) and should not be frozen.

• The tablets must be kept out of reach of children.

For Patients

What Is Multidrug-Resistant Tuberculosis?

Multidrug-resistant tuberculosis (MDR-TB) is a life-threatening infectious disease caused by a resistant strain of Mycobacterium tuberculosis. Multidrug-resistant Mycobacterial strain refers to Mycobacterium that does not respond to treatment by first-line antitubercular drugs such as Rifampin and Isoniazid. In multi-drug resistant TB, even two or more potent anti-TB drugs cannot kill or control Mycobacterial growth. MDR-TB is emerging as a serious global health threat and is more prevalent in India, Eastern Europe, and China.

Multidrug-resistant TB spreads in the same way as drug-susceptible tuberculosis spreads. It spreads as a droplet infection through the air from an infected person to a normal person. The infection enters the air as droplets when a person harboring MDR-TB coughs, sneezes, or speaks. It gets transmitted to nearby people when they breathe the infected air. Multidrug-resistant TB primarily affects the lungs and spreads to other body parts, such as the kidneys, the spine, and the brain.

The treatment of MDR-TB is more challenging and complex because it involves intense chemotherapy and extensive monitoring. Also, the existing second-line drugs are less effective and cause more side effects. MDR-TB therapy takes more years to get cured than the usual form of TB and becomes an economic burden on the affected individuals. Multidrug-resistant tuberculosis results in fatal complications and death due to improper treatment. The Discovery of new antitubercular drugs such as Bedaquiline has greatly increased the efficacy of multidrug-resistant tuberculosis treatment.

What Is Bedaquiline?

Bedaquiline is a diarylquinoline antibiotic prescribed for individuals aged 12 years and above who have developed multi-drug resistant tuberculosis (MDR-TB) in the lungs. Furthermore, it is prescribed when other available therapeutic options are not curing the disease. It is the first novel drug that belongs to a new class of antimycobacterial drugs. This drug aims at treating multidrug-resistant tuberculosis by attacking the resistant strain in a different and specific way. It is a potent antimycobacterial agent and is used in combination with other antituberculosis drugs to treat multidrug-resistant tuberculosis.

Bedaquiline is recommended for treating MDR-TB because of its shorter therapy time, high efficacy, and relatively safe than other second-line drugs. Bedaquiline expresses a unique antimycobacterial activity that disrupts the energy production in the TB bacteria and kills the Mycobacterium. This novel drug action reduces the treatment duration and increases the efficacy of multidrug-resistant tuberculosis therapy.

Adverse Side Effects

Many common adverse side effects have been reported in Bedaquiline therapy.

Some of them are as follows -

• Nausea.

• Arthralgia.

• Headache.

• Hemoptysis.

• Chest pain.

• Anorexia.

• Rashes in extremities.

• Cardiovascular complications such as QT prolongation.

• Elevated levels of liver enzymes such as hepatic transaminases.

• Unilateral deafness.

• Hyperuricemia.

• Neuropathy.

• Fever.

• Diarrhea.

• Vomiting.

• Headache.

• Weight loss.

• Insomnia.

• Fatigue.

• Dizziness.

• Tinnitus.

• Ataxia.

• Blurred vision.

What Are the Precautions to Be Followed While Using Bedaquiline?

Bedaquiline is a recently approved antimycobacterial drug to treat multidrug-resistant tuberculosis. Adverse cardiac side effects and hepatic drug toxicities to Bedaquiline are reported in clinical practice. Following essential precautionary measures would ensure safe and successful Bedaquiline therapy.

• Any pre-existing cardiac conditions, heart failure, or liver problems should be reported before the therapy.

• Tests to evaluate cardiac functioning, such as ECG (electrocardiogram), should be obtained before initiating Bedaquiline therapy.

• Individuals with liver problems should obtain liver function tests before taking Bedaquiline.

• Cardiac function tests should be repeated after 22 or 24 weeks of Bedaquiline therapy.

• For an effective therapy outcome, the tablet should be taken as a whole with water, and food should be taken before it.

• Metabolic parameters such as serum potassium, magnesium, and calcium levels must be monitored regularly during the treatment.

• Bedaquiline should not be taken on an empty stomach.

• Alcohol and hepatotoxic drugs must be avoided during Bedaquiline therapy.

• Any signs and symptoms of adverse drug side effects must be immediately reported to the doctor.

• Non-adherence to the treatment regime or discontinuing the therapy could lead to treatment failure or relapse and acquired drug resistance to Beadquiline.

• The use of Bedaquiline in conditions like pregnancy and lactation has not been completely investigated. Hence such conditions must be informed before the therapy.

• On missing the dose in the first two weeks of Bedaquiline therapy, patients should not repeat the missed dose and could continue with the regular dosing schedule that follows.

• From the third week, if a single dose of 200 milligrams is missed, the missed dose should be administered as soon as possible. The three-times-a-week regime should subsequently be followed. A total dose of 600 milligrams should not be exceeded in seven days.

• Accidental overdose must be reported to the doctor immediately.

For Doctors

Clinical Pharmacology of Bedaquiline

Mechanism of Action

Bedaquiline exhibits a unique antimycobacterial mechanism by blocking the Mycobacterial adenosine triphosphate synthase enzyme. This ATP synthase is an essential enzyme in synthesizing ATP and energy generation in Mycobacterium tuberculosis. Bedaquiline is highly selective to Mycobacterial ATP synthase enzyme compared to its homologous eukaryotic enzyme with a selectivity Index of more than 20,000. Thus, Bedaquilione produces target-specific toxicity in the Mycobacterial cells. The following steps describe the antitubercular activity of Bedaquiline.

• Bedaquiline binds to the proteolipid, oligomeric subunit-c of Mycobacterial ATP synthase enzyme.

• This binding blocks proton pump activation and inhibits the functioning of ATP synthase.

• Failure to generate energy molecules (ATP) eventually leads to mycobacterial cell death.

• The gene (atpE) that codes for the subunit-c in ATP synthase is a highly conserved amino acid sequence and is not subjected to frequent mutations. Thereby, the Mycobacterium isolates cannot develop resistance to Bedaquiline.

• This property renders the Mycobacterium isolates more susceptible to Bedaquiline and enhances the effective use of Bedaquiline in treating MDR–TB.

Pharmacodynamics

The required minimal inhibitory concentration (MIC) for inhibiting the growth of Mycobacterium tuberculosis ranges from 0.002 micrograms per milliliter to 0.06 micrograms per milliliter. The mean value MIC of 50 for Bedaquiline is 0.03 microgram per milliliter. Mycobacteria having minimum ATP stores, especially dormant and nonreplicating Mycobacteria, show increased susceptibility to Bedaquiline.

Chemical Taxonomy of Bedaquiline:

• Kingdom: Organic compounds.

• Super Class: Phenylpropanoids and polyketides.

• Class: Stilbenes.

• Sub Class: Data not available.

• Direct Parent Compound: Stilbenes.

• Alternative Parent Compound: Quinolones and their derivatives, Haloquinolines, Naphthalenes, Aryl bromides, Pyridines and their derivatives, Heteroaromatic compounds.

• Substituents: 1,3-amino alcohol, alkyl aryl ether, aromatic alcohol, aryl bromide, aromatic hetero polycyclic compound.

• Molecular Framework: Aromatic hetero polycyclic compounds.

• External Descriptors: Tertiary alcohol, naphthalenes (CHEBI:72292), organobromine compound, aromatic ether, quinolines, tertiary amino compound.

Pharmacokinetics

• Bedaquiline is taken orally as a 100 milligrams tablet along with food.

• The presence of food increases its bioavailability by two-fold than its absence under fasting conditions.

• Absorption - After a single intake of the oral dose, it takes five hours (post-dose) to reach the maximum plasma concentrations (Cmax).

• On administering 400 milligrams of Bedaquiline once daily for one week, Cmax reaches 5.5 micrograms per milliliter.

• Cmax and AUC (area under the plasma concentration-time curve) increase 1.75 times higher than the loading dose (400 milligrams).

• Distribution - The plasma protein binding capacity of Bedaquiline is more than 99.9 percent.

• Its volume of distribution (Vd) in the plasma (central compartment) is 164 L.

• On reaching maximum plasma concentration, Bedaquiline levels in plasma decrease tri-exponentially.

• Its effective half-life is 24 to 30 hours, and its terminal half-life is nearly four to five months.

• Metabolism - Bedaquiline is metabolized in the liver. It is oxidized by the CYP3A4 (Cytochrome P450 3A4) enzyme to form N-mono desmethyl metabolite (M2).

• M2 is four to six times less potent when compared to the parent drug compound. Plasma levels of M2 contribute to prolonged QT intervals.

• CYP3A4 enzyme-inducing agents decrease the efficacy of Bedaquiline, whereas substances that inhibit this enzyme increase its risk of toxicity.

• Elimination - Bedaquiline is primarily eliminated in the feces. Its renal clearance remains insignificant.

Toxicity

Clinical studies have reported the potential risk of toxicity and adverse reactions while using Bedaquiline. FDA has placed Bedaquiline on the black-box warning list because of its potential risk of inducing toxic complications and higher mortality risk. Black-box warning for Bedaquiline is attributed to its adverse effect on altering cardiac electrical impulses, leading to increased duration of QT interval. This causes abnormal contractions of heart muscles and fatal cardiac rhythms.

The toxic adverse reactions associated with Bedaquiline therapy are as follows -

• Bedoquiline prolongs the cardiac QT interval, particularly in patients with already existing cardiac insufficiencies such as hypothyroidism, uncompensated cardiac failure, and bradyarrhythmias.

• Ventricular arrhythmias.

• Serum calcium, potassium, and magnesium levels alter, leading to cardiac complications.

• Syncope.

• Hepatotoxicity and liver tenderness.

• Fatigue.

• Anorexia.

• Nausea.

• Jaundice and dark urine.

• Hepatomegaly.

• Elevated levels of liver enzymes such as alkaline phosphatase and aminotransferase.

• Bilirubin levels are increased.

• Bedaquiline does not initiate renal injury but could enhance renal dysfunction in existing renal disorders.

• Risk of increased mortality rate.

Drug interactions

The drug interactions of Bedaquiline are mainly attributed to pharmacological factors such as pharmacodynamics and pharmacokinetics.

• Concomitant use of Bedaquline with drugs that increase QT interval leads to a synergistic effect on QT interval.

• The oxidative metabolism of Bedaquiline is mediated by cytochrome P450 3A4 enzyme.

• Concomitant use of Bedaquline and cytochrome P450 inducers increases the metabolism of Bedaquiline, and its efficacy is reduced.

• Cytochrome P450 inhibitors increase the bioavailability of Bedaquiline and lead to increased adverse side effects of Bedaquiline.

Some of the reported drug-drug interactions of Bedaquiline are as follows -

• Drugs such as Clofazimine, fluoroquinolones, and macrolides increase QT interval and, when used along with Bedaquiline, could lead to an additive effect on QT interval.

• Ketoconazole is an active cytochrome P450 inhibitor that increases the risk of adverse toxicities caused by Bedaquiline.

• Drugs such as Rifampin which are potent inducers of CYP3A4 could reduce the therapeutic efficacy of Bedaquiline.

• Interactions with Ritonavir (a potent CYP3A4 inhibitor used in HIV therapy) increase the drug toxicity of Bedaquiline.

Preventive Measures for Doctors

Bedaquiline is a novel antitubercular compound that inhibits Mycobacterium tuberculosis growth and shows effective bactericidal activity for longer. Bedaquiline has been identified as a potential drug that fulfills all the clinical criteria for treating multidrug-resistant tuberculosis and also minimizes the risk of developing resistance to anti-TB drugs in the standard antituberculosis regime. Clinical practitioners should follow the following precautionary measures to ensure the safe and effective use of Bedaquiline in MDR-TB therapy.

• It is mandatory to use Bedaquiline only on patients who do not respond to existing anti-TB drugs and have no other therapeutic options.

• Bedaquiline therapy should always be monitored with microbiologic culture and analysis of drug susceptibility with sputum specimens, each submitted periodically for culture every month throughout the treatment and after the sputum conversion to a negative culture.

• Healthcare professionals must be aware of Bedaquiline’s effect on cardiac electrical activity and its potential abnormal cardiac contractions.

• Concurrent use of Bedaquiline, along with other QT-prolonging drugs, must be avoided.

• Electrocardiograms (ECGs) must be monitored regularly during concomitant therapy.

• Healthcare providers must have a thorough knowledge of its adverse effects and be equipped to handle any toxic episodes.

• Any positive culture specimen should be immediately reported to an authenticated national public health laboratory to monitor Bedaquiline's effectiveness.