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药品详细

Bedaquiline(和吡嗪酰胺)

化学结构式图
中文名
和吡嗪酰胺
英文名
Bedaquiline
分子式
C32H31BrN2O2
化学名
(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
分子量
Average: 555.505
Monoisotopic: 554.156890893
CAS号
843663-66-1
ATC分类
J04A 未知
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Bedaquiline is a bactericidal antimycobacterial drug. Chemically it is a diarylquinoline. FDA approved on December 28, 2012.

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    参考
    Synthesis Reference Not Available
    General Reference
    1. Matteelli A, Carvalho AC, Dooley KE, Kritski A: TMC207: the first compound of a new class of potent anti-tuberculosis drugs. Future Microbiol. 2010 Jun;5(6):849-58. doi: 10.2217/fmb.10.50. Pubmed
    剂型
    规格
    化合物类型
    Type small molecule
    Classes Not Available
    Substructures Not Available
    适应症
    药理
    Indication Bedaquiline is indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB).
    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 to 6-fold lower) compared to the parent compound. M2 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. Furthermore, bacteria that have smaller ATP stores (usually in dormant, nonreplicating bacilli) are more susceptible to bedaquiline.
    Mechanism of action Bedaquiline is a diarylquinoline antimycobacterial drug that inhibits the proton pump of mycobacterial ATP (adenosine 5'-triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis. Bacterial death occurs as a result of bedaquiline.
    Absorption Tmax, oral dose = 5 hours; Food increases the oral bioavailability. AUC increases proportionally up to the highest dose studied in healthy volunteers. When 400 mg of bedaquiline is administered once daily for a week, the peak plasma concentration (Cmax) is 5.5 μg/ml and an AUC of 64.75 μgh/ml.
    Volume of distribution

    Vd, central compartment = 164 L
    Protein binding >99.9 bound to plasma proteins.
    Metabolism
    Bedaquiline is hepatically metabolized. The main enzyme involved is CYP3A4 which metabolizes bedaquiline into the N-monodesmethyl metabolite (M2). This metabolite is 4 to 6-times less active in terms of antimycobacterial potency.
    Route of elimination Bedaquiline is primarily elimination in the feces. The urinary excretion of unchanged bedaquiline was < 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant.
    Half life Terminal elimination half-life, bedaquiline and M2 = 5.5 months. This long half-life suggests slow release of bedaquiline and M2 from peripheral tissues.
    Clearance Not Available
    Toxicity The most common adverse reactions reported in ≥10% of patients treated with bedaquiline are nausea, arthralgia, and headache.
    Affected organisms
    • Mycobacterium tuberculosis
    Pathways Not Available
    理化性质
    Properties
    State solid
    Experimental Properties
    Property Value Source
    water solubility Insoluble FDA label
    Predicted Properties
    Property Value Source
    water solubility 1.93e-04 g/l ALOGPS
    logP 6.37 ALOGPS
    logP 7.13 ChemAxon
    logS -6.5 ALOGPS
    pKa (strongest acidic) 13.61 ChemAxon
    pKa (strongest basic) 8.91 ChemAxon
    physiological charge 1 ChemAxon
    hydrogen acceptor count 4 ChemAxon
    hydrogen donor count 1 ChemAxon
    polar surface area 45.59 ChemAxon
    rotatable bond count 8 ChemAxon
    refractivity 154.02 ChemAxon
    polarizability 57.29 ChemAxon
    药物相互作用
    Drug Interaction
    Ketoconazole Strong CYP3A4 inhibitors may increase exposure of bedaquiline. Monitor concomitant therapy closely.
    Rifampin Strong CYP3A4 inducers may decrease exposure of bedaquiline. Co-administration should be avoided.
    食物相互作用
    • When administered with food, relative bioavailability increases 2-fold

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