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Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
Bedaquiline (BDQ) is a highly water-insoluble weak base (log P 7.3, pKa 8.91–13.61, MW 555.505). It is a synthetic diarylquinoline that inhibits the mycobacterial ATP synthase.228 Wild-type MICs to BDQ range from 0.008 to 0.25 μg/mL.229 The spontaneous rate of mutations conferring resistance is approximately 1 in 10.8,57 Mutations in the atpE gene selected in vitro are clearly associated with high-level resistance whereas SNPs in the gene rv0678, a regulator of the MmpL5 efflux pump, are found in 6% of clinical MDR-TB isolates prior to treatment but are inconsistently related to changes in MIC.230
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Peter D O Davies, Stephen B Gordon, Geraint Davies, Clinical Tuberculosis, 2014
Abdullah Alsultan, Charles A. Peloquin
The diarylquinoline bedaquiline (R207910, TMC207) is chemically related to the malaria drug chloroquine and is undergoing phase II testing for TB [160–162]. Published data are very promising, and the drug was conditionally approved by the US FDA. A phase II study in MDR-TB patients showed that adding bedaquiline to a standard MDR-TB regimen produces more rapid culture conversion [163]. Bedaquiline has a unique mechanism of action, targeting the bacterial ATP synthase. Therefore, there is no cross-resistance with other TB drugs [160]. It is equally active against drug-sensitive and drug-resistant strains of M. tuberculosis, with an MIC of about 0.03 μg/mL, and it is active against many other types of mycobacteria. Bedaquiline has an active metabolite with a very long elimination half-life. Plasma concentrations of bedaquiline are significantly reduced by concurrent use of RIF.
Prospects of Pre-clinical [6.6.0] Bicyclic Nitrogen Heterocycles in the Treatment of Tuberculosis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Neha P. Agre, Mariam S. Degani, Sanjib Bhakta
Quinoline is a bicyclic [6.6.0] nitrogen heterocyclic scaffold, which is the core of a number of anti-TB drugs, pre-clinical and clinical candidates. Bedaquiline (7) (Figure 1), a diarylquinoline, is the newest member of the class of anti-TB drugs and has been recently launched in the market for the treatment of MDR-TB infections (Fox and Menzies 2013). The quinoline scaffold is also present in fluoroquinolones (Figure 1), the largest class of second line TB drugs (Asif 2013). The agent TBAJ-587 (8) (Figure 1), a quinoline containing pre-clinical candidate, is a next-generation diarylquinoline derivative designed to possess bedaquiline’s impressive anti-TB activities with improved pharmacological properties. The compound OPC-167832 (under patent, complete structure not disclosed) is a quinoline containing phase-I clinical trial candidate and an inhibitor of decaprenylphophoryl-β-D-ribose 2’-oxidase (DprE1), an enzyme involved in the cell-wall metabolism. The newest member of the fluoroquinolone class showing promising anti-TB activity is DC-159a (9) (Figure 1), which is currently undergoing pre-clinical trials (Dhiman and Singh 2018). Furthermore, the TB alliance pipeline has three new drug combinations in clinical trials, all containing bedaquiline together with an additional fluoroquinolone: bedaquiline (7) + pretonamid (10) + pyrazinamide (11); bedaquiline (7) + pretonamid (10) + moxifloxacin (12) + pyrazinamide (11) (phase II advanced), and bedaquiline (7) + pretonamid (10) + linezolid (13) (phase 3) (Li et al. 2017). Some attempts have been made to repurpose already available non-toxic drugs in order to circumvent the time and investment required to discover and develop new drugs (Maitra et al. 2018, Maitra and Bhakta 2014). Anti-malarials constitute one such therapeutic class explored for their anti-tuberculosis potential. Mefloquine (14) has shown to have a good anti-TB potential (Bermudez and Meek 2014). Derivatives of mefloquine (Mao et al. 2010), primaquine (15) (Pavić et al. 2018) and quinine (16) (Tukulula et al. 2012) have also shown to possess some promising anti-TB activity. Quinoline containing anti-TB drugs and pre-clinical/clinical candidates.
The pharmacotherapeutic management of pulmonary tuberculosis: an update of the state-of-the-art
Published in Expert Opinion on Pharmacotherapy, 2022
Ginenus Fekadu, Dilys Yan-wing Chow, Joyce H.S. You
Bedaquiline is a diarylquinoline that inhibits mycobacterial ATP synthase, and it was the first approved novel oral anti-TB agent in 40 years for the enhanced sputum culture conversion rate in MDR-TB patients demonstrated in clinical trials. In a stage 1 of a phase 2b randomized trial in patients with newly diagnosed MDR-TB, adding 8-week bedaquiline to a preferred five-drug, second-line background regimen showed improvement in antibacterial activity [27,28]. Bedaquiline became a potential game-changer of an all-oral shorter regimen for MDR-TB. In the stage 2 of the phase 2b study, 24-week bedaquiline or placebo was added to a preferred 5-drug background regimen in 160 newly diagnosed MDR-TB patients [29]. When compared with placebo, bedaquiline shortened the median time to culture conversion from 125 days to 83 days, improved the culture conversion rate at 24 weeks (79% versus 58%, p = 0.008) and at 120 weeks (62% versus 44%, p = 0.04), and achieved higher cure rate at 120 weeks (58% versus 32%, p = 0.003).
Safety implications of combined antiretroviral and anti-tuberculosis drugs
Published in Expert Opinion on Drug Safety, 2020
Maddalena Cerrone, Margherita Bracchi, Sean Wasserman, Anton Pozniak, Graeme Meintjes, Karen Cohen, Robert J Wilkinson
Perhaps the most important advance in DR-TB treatment has been the introduction of bedaquiline into treatment programs. A diarylquinoline, bedaquiline has a unique mechanism of action by inhibiting mycobacterial ATP synthesis. Due to potent antimycobacterial activity, bedaquiline enables DR-TB treatment shortening resulting in improved outcomes, including survival in a large retrospective cohort analysis [71]. Although well tolerated, it is associated with prolongation of the QT interval. Another drawback is that bedaquiline is primarily metabolized by CYP3A4 [72], and is thus subject to drug–drug interactions with ART drugs that modulate activity of this isoenzyme. Drugs that inhibit CYP3A4, such as ritonavir-boosted PIs [73,74], may lead to increased bedaquiline concentrations, potentially increasing the risk for toxicity, especially QT prolongation. CYP3A4 inducers, especially RIF, may affect the PK of bedaquiline in the opposite direction, potentially leading to reduced efficacy and resistance selection.
Prevention and treatment of tuberculosis in solid organ transplant recipients
Published in Expert Review of Anti-infective Therapy, 2020
Cybele L. Abad, Raymund R. Razonable
Bedaquiline is a newly approved diarylquinoline which inhibits the c subunit of ATP synthase, thereby decreasing intracellular ATP levels. An attractive feature of bedaquiline is its equipotent activity against both replicating and dormant TB bacilli [96,97]. Bedaquiline is highly active against the TB bacilli, including those that are resistant to first-line drugs, displaying minimal inhibitory concentrations equal to or lower than those of INH and RIF. It has been tested in Phase II clinical trials on newly diagnosed MDR‐TB cases and its addition to standard therapy for MDR‐TB reduced the time to culture conversion (e.g. time to culture negativity) and greatly increased the proportion of patients whose sputum became culture‐negative [98]. Another feature of bedaquiline is its unusually long half‐life, a desirable feature for the inclusion of this drug in an intermittent regimen [99]. However, bedaquiline also accumulates in tissues; therefore, care must be taken to avoid carry‐over effects when measuring its activity [100]. Bedaquiline has a black‐box warning due to its potential to induce arrhythmia [101].