Indications
Bedaquiline is prescribed as a component of combination therapy for the treatment of pulmonary tuberculosis in adult and pediatric patients aged 5 years and older who weigh at least 15 kg. This medication specifically targets strains of Mycobacterium tuberculosis that exhibit resistance to rifampin and isoniazid. The approval for this indication was granted through the FDA's accelerated approval process, based on the time to sputum culture conversion. Ongoing approval is dependent on further confirmation and description of clinical benefits in additional trials.
Pharmacodynamics
Bedaquiline undergoes oxidative metabolism, resulting in the production of the N-monodesmethyl metabolite (M2). Despite the presence of M2, it contributes minimally to clinical efficacy because of its lower antimycobacterial activity and reduced exposure levels in humans compared to the parent compound. However, M2 is associated with alterations in the QT interval. Bedaquiline exhibits inhibition of Mycobacterium tuberculosis with a minimal inhibitory concentration (MIC) ranging from 0.002 to 0.06 μg/ml and an MIC50 of 0.03 μg/ml. While naturally resistant bacterial strains are rare, resistance can develop through modifications to the atpE target gene or upregulation of the MmpS5-MmpL5 efflux pump, resulting in elevated MIC values. Additionally, preclinical studies have observed resistance-related increases in MIC values.
Absorption
Following the administration of bedaquiline at the recommended dosing schedule, the peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC24h) are 1.659 μg/ml and 25.863 μg.h/ml, respectively. A single oral dose of bedaquiline reaches maximum plasma concentrations approximately five hours post-dose, with Cmax and AUC increasing proportionally up to doses of 700 mg. The bioavailability of bedaquiline is significantly enhanced when taken with a standard meal containing approximately 22 grams of fat, doubling its absorption compared to fasting conditions. Therefore, it is advised that bedaquiline be taken with food to optimize its oral bioavailability.
Metabolism
The metabolism of bedaquiline is predominantly mediated by the CYP3A4 isoenzyme, leading to the formation of the N-monodesmethyl metabolite (M2). Understanding this metabolic pathway is crucial for assessing potential drug interactions and optimizing dosing regimens to ensure therapeutic efficacy while minimizing the risk of adverse effects.
Mechanism of Action
Bedaquiline, a diarylquinoline antimycobacterial agent, functions by targeting mycobacterial ATP synthase, a critical enzyme for energy production in Mycobacterium tuberculosis. It specifically binds to subunit c of the enzyme, thereby inhibiting ATP synthesis and disrupting the bacterium's energy generation process. This inhibition of ATP production is crucial for the effective management of tuberculosis, as it impairs the pathogen's ability to survive and proliferate.
