SIRTURO 20 mg

Indications

• Pulmonary multidrug-resistant tuberculosis
• Tuberculosis resistant to first-line drugs

Dosage

Children: Refer to BNF for Children for specific paediatric dosing recommendations.

Adults: Initially, 400 mg once daily for 2 weeks, followed by 200 mg 3 times a week for 22 weeks, ensuring intervals of at least 48 hours between doses.

Mechanism of action

Bedaquiline inhibits mycobacterial ATP synthase by binding to subunit c of the enzyme, which is essential for ATP generation in Mycobacterium tuberculosis. This inhibition leads to a lack of ATP synthesis, resulting in bacteriostasis and preventing the bacteria from generating the energy required for growth and replication.

Pharmacodynamics

Bedaquiline exhibits its antimicrobial activity primarily through the inhibition of ATP synthesis in Mycobacterium tuberculosis. It has a minimal inhibitory concentration (MIC) ranging from 0.002 to 0.06 μg/ml, with its effectiveness increasing against bacteria with lower ATP stores, such as dormant or non-replicating bacilli. The drug undergoes oxidative metabolism, producing a metabolite (M2) that is less active than the parent compound, yet its plasma concentrations are associated with QT prolongation risks.

Pharmacokinetics

Bedaquiline is absorbed after oral administration, with a half-life that allows for once-daily dosing. It undergoes extensive hepatic metabolism, primarily by CYP3A4, which can interact with other medications. Its pharmacokinetic profile is influenced by various factors, including drug interactions that can affect its efficacy and safety.

Contra-indications

• QTc interval more than 500 milliseconds
• ventricular arrhythmia

Adverse effects

• arthralgia
• diarrhoea
• dizziness
• headache
• hepatic function abnormal
• myalgia
• nausea
• QT interval prolongation
• syncope
• vomiting

Interactions

• Severe: antifungals (azoles), dabrafenib, mitotane, non-nucleoside reverse transcriptase inhibitors (NNRTIs), St John's wort, rifampicin
• Unknown: dronedarone, clofazimine, cobicistat, crizotinib

Precautions

• Caution in patients with auditory impairment
• Caution in patients with renal impairment (risk of nephrotoxicity and ototoxicity)
• Caution in patients with hepatic impairment (avoid in severe impairment)
• Monitor renal, hepatic, auditory, and vestibular function and electrolytes

Pregnancy

Manufacturer advises use only if potential benefit outweighs risk-teratogenic in animal studies.

Breast-feeding

Manufacturer advises caution-no information available.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• 100 mg Sirturo tablets
• Gastro-resistant granules

Mechanism of action

Bedaquiline 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._. Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multidrug-resistant tuberculosis in decades. Though BDQ has shown excellent efficacy in clinical trials, its early bactericidal activity during the first week of chemotherapy is minimal. Here, using microfluidic devices and time-lapse microscopy of Mycobacterium tuberculosis, we confirm the absence of significant bacteriolytic activity during the first 3-4 days of exposure to BDQ. BDQ-induced inhibition of ATP synthesis leads to bacteriostasis within hours after drug addition. Transcriptional and proteomic analyses reveal that M. tuberculosis responds to BDQ by induction of the dormancy regulon and activation of ATP-generating pathways, thereby maintaining bacterial viability during initial drug exposure. BDQ-induced bacterial killing is significantly enhanced when the mycobacteria are grown on non-fermentable energy sources such as lipids (impeding ATP synthesis via glycolysis). Our results show that BDQ exposure triggers a metabolic remodelling in mycobacteria, thereby enabling transient bacterial survival. 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. Infections with Mycobacterium tuberculosis are substantially increasing on a worldwide scale and new antibiotics are urgently needed to combat concomitantly emerging drug-resistant mycobacterial strains. The diarylquinoline TMC207 /bedaquiline/ is a highly promising drug candidate for treatment of tuberculosis. This compound kills M. tuberculosis by binding to a new target, mycobacterial ATP synthase. In this study we used biochemical assays and binding studies to characterize the interaction between TMC207 and ATP synthase. We show that TMC207 acts independent of the proton motive force and does not compete with protons for a common binding site. The drug is active on mycobacterial ATP synthesis at neutral and acidic pH with no significant change in affinity between pH 5.25 and pH 7.5, indicating that the protonated form of TMC207 is the active drug entity. The interaction of TMC207 with ATP synthase can be explained by a one-site binding mechanism, the drug molecule thus binds to a defined binding site on ATP synthase. TMC207 affinity for its target decreases with increasing ionic strength, suggesting that electrostatic forces play a significant role in drug binding. Our results are consistent with previous docking studies and provide experimental support for a predicted function of TMC207 in mimicking key residues in the proton transfer chain and blocking rotary movement of subunit c during catalysis. Furthermore, the high affinity of TMC207 at low proton motive force and low pH values may in part explain the exceptional ability of this compound to efficiently kill mycobacteria in different microenvironments.

Pharmacodynamics

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) than the parent compound. However, M2 plasma concentrations appeared to correlate with QT prolongation. Bedaquiline inhibits mycobacterial TB at a minimal inhibitory concentration (MIC) from 0.002-0.06 μg/ml and with a MIC₅₀ of 0.03 μg/ml. The proportion of naturally resistant bacteria is low, estimated to be in one strain over 10⁷/10⁸ bacteria. Bacteria that have smaller ATP stores (such as dormant, nonreplicating bacilli) are more susceptible to bedaquiline. Additionally, bedaquiline is also effective against nontuberculous mycobacteria, with MICs ranging from 0.06 to 0.5 μg/ml. A potential for the development of resistance to bedaquiline in M. tuberculosis exists. Modification of the atpE target gene, and/or upregulation of the MmpS5-MmpL5 efflux pump (Rv0678 mutations) 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 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 0.5 micrograms per mL.