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.
贝达喹啉在肝脏中代谢。主要涉及的酶是CYP3A4，它将贝达喹啉代谢为N-单脱甲基代谢物（M2）。这个代谢物在抗分枝杆菌效力方面比原药低4到6倍。
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.
CYP3A4 was the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2), which is 4 to 6-times less active in terms of antimycobacterial potency. Based on preclinical studies, bedaquiline is mainly eliminated in 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. After reaching Cmax, bedaquiline concentrations decline tri-exponentially. The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months. This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from peripheral tissues.
After a single dose the mean AUC0-24 hr of the major metabolite M2 was 2 to 7-fold higher than AUC0-24 hr of bedaquiline in mice and was generally similar to 2-fold lower in rats and dogs.
Bedaquiline is a recently approved drug for the treatment of multidrug-resistant tuberculosis. Adverse cardiac and hepatic drug reactions to bedaquiline have been noted in clinical practice. The current study investigated bedaquiline metabolism in human hepatocytes using a metabolomic approach. Bedaquiline N-demethylation via CYP3A4 was confirmed as the major pathway in bedaquiline metabolism. In addition to CYP3A4, we found that both CYP2C8 and CYP2C19 contributed to bedaquiline N-demethylation. The Km values of CYP2C8, CYP2C19, and CYP3A4 in bedaquiline N-demethylation were 13.1, 21.3, and 8.5 uM, respectively. We also identified a novel metabolic pathway of bedaquiline that produced an aldehyde intermediate. In summary, this study extended our knowledge of bedaquiline metabolism, which can be applied to predict and prevent drug-drug interactions and adverse drug reactions associated with bedaquiline.
No chiral conversion of bedaquiline occurred in vivo after administration of bedaquiline to mice, rats, dogs, monkeys and humans. In hepatocytes and subcellular fractions from preclinical species and humans, the in vitro metabolism of (14)C-bedaquiline was via Phase I reactions and the most important pathway was N-demethylation to M2, which was followed by a second N-demethylation to M3, oxidation and epoxidation. M2 was the major circulating metabolite in all preclinical species as determined by radioactivity profiling and LC-MS/MS in the animals. No mass balance study with radiolabelled bedaquiline has been conducted in humans. It can therefore not be excluded that additional undetected metabolites may be formed in humans that are not formed in the animal species. M2-AUC0-24 hr plasma levels were generally comparable to 2-fold lower than those of bedaquiline in rats and dogs upon repeated administration of bedaquiline, and 3.5- to 4.5-fold lower in human subjects with MDR-TB. In addition to M2 and M3, a hydroxylated derivative of M2 (M20) and a dihydrodiol derivative of M2 (M11), were detected in human plasma. These two metabolites were also found in rats and dogs at similar relative concentrations.
IDENTIFICATION AND USE: Bedaquiline is a white solid. It is used as a antitubercular medication. HUMAN EXPOSURE AND TOXICITY: An increased risk of death was observed in patients receiving bedaquiline in a placebo-controlled clinical trial. In this study, there were 9 deaths in bedaquiline-treated patients; one death occurred during the 24 weeks of bedaquiline therapy and the median time to death for the other 8 patients was 329 days after the last dose of bedaquiline. Five of the 9 deaths in bedaquiline-treated patients and both deaths in placebo-treated patients were related to tuberculosis. The explanation for the imbalance in deaths in this study is not known; no correlation was demonstrated between death and sputum culture conversion, relapse, susceptibility to other antituberculosis drugs, HIV status, or disease severity. Bedaquiline and the M2 metabolite are cationic amphiphilic substances and induce phospholipidosis. The cells of the monocytic phagocytic system are affected in all species. Data from in vitro studies using human monocyte cell-line indicated that the phospholipidogenic potential was highest for the M2 metabolite followed by M3 and the parent compound. ANIMAL STUDIES: In mouse and rat, single oral doses of 800 mg/kg produced lethality preceded by signs of general toxicity. Mortalities in mouse and dog after single and repeated doses were principally attributed to skeletal muscle/myocardial degeneration and/or pancreatitis. Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. In embryofetal toxicity studies conducted in rat and rabbit bedaquiline appeared to have no adverse effects on the embryonal development and the incidence of variations and malformations in fetuses in bedaquiline groups were within normal ranges. Exposure to bedaquiline and the M2 metabolite in rat at the high dose was considerable (up to 6-7 times higher compared with expected human exposure), while in rabbit a maximum exposure ratio of 2 were achieved. However, in rabbit the high dose of 100 mg/kg caused deaths, one abortion and increases in pre and postimplantation losses. Bedaquiline had no effect on fertility in females up to the highest dose tested, 24 mg/kg. Male fertility appeared to be decreased with a NOAEL of 5 mg/kg. No mutagenic or clastogenic effects were detected in the in vitro non-mammalian reverse mutation (Ames) test, in vitro mammalian (mouse lymphoma) forward mutation assay and an in vivo mouse bone marrow micronucleus assay.
Liver test abnormalities occur in 8% to 12% of patients treated with multiple drug regimens that include bedaquiline. These abnormalities are usually asymptomatic, mild-to-moderate in severity and self-limited in duration. In many instances, it is difficult to determine which of the antituberculosis medications accounts for the abnormalities, but monitoring of liver tests at monthly intervals is recommended during bedaquiline therapy. Clinically apparent liver injury has been reported with bedaquiline therapy, but the clinical features, course and outcome of these cases has not been described. At least three deaths from end stage liver disease have been described in patients taking bedaquiline, but the attribution of the hepatic failure to bedaquiline has been questioned. The management of multidrug resistant tuberculosis is challenging and should be under the direction of physicians with expertise in tuberculosis therapy.
◉ Summary of Use during Lactation:Data from two women taking bedaquiline and one of their breastfed infants indicate that exposure of the infant to the drug via breastmilk is substantial, with one infant having a therapeutic serum level. The clinical consequences of this exposure are unknown. The drug could protect the infant from multidrug-resistant tuberculosis, or could result in adverse effects. If bedaquiline is required by the mother, it is not a reason to discontinue breastfeeding. Monitor breastfed infants for adverse reactions, such as inadequate weight gain, liver toxicity, nausea, arthralgia, headache, hemoptysis, and chest pain.
◉ Effects in Breastfed Infants:A woman who was co-infected with HIV and rifampin-resistant tuberculosis took bedaquiline (dosage not stated) as part of her antituberculosis regimen, which consisted of pyrazinamide and other unnamed drugs. At the 1-month follow-up, the infant was small and not gaining weight well, but the mother was nauseated from her medication regimen and had also lost weight. Six months later after completion of the mother’s therapy, her infant’s weight was increasing, following the normal trajectory of the growth chart, and reaching her developmental milestones.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Pharmacologic interaction (increased risk of QT interval prolongation). Concomitant use with other drugs that prolong the QT interval (e.g., clofazimine, fluoroquinolones, macrolides) may result in additive or synergistic effects on the QT interval.
Bedaquiline is metabolized primarily by cytochrome P-450 (CYP) isoenzyme 3A4. Concomitant use of bedaquiline with potent inhibitors of CYP3A4 (e.g., ketoconazole) may increase the area under the concentration-time curve (AUC) of bedaquiline and increase the risk of adverse effects associated with the drug. Concomitant use of bedaquiline and systemic drugs that are potent inhibitors of CYP3A4 for a duration longer than 14 consecutive days should be avoided, unless the benefits of concomitant use outweigh the risks. Patients receiving such concomitant therapy should be monitored for bedaquiline-related adverse effects. Concomitant use of bedaquiline with potent inducers of CYP3A4, including rifamycins (e.g., rifampin, rifapentine, rifabutin), may reduce the AUC of bedaquiline and decrease the therapeutic effects of the drug. Concomitant use of bedaquiline with rifamycins or other potent inducers of CYP3A4 should be avoided.
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.
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.
来源:DrugBank
吸收、分配和排泄
分布容积
Vd, central compartment = 164 L
分布容积，中央室 = 164 升
Vd, central compartment = 164 L
来源:DrugBank
吸收、分配和排泄
Bedaquiline 是一种用于治疗肺多药耐药结核分枝杆菌感染的新药，与其他药物联合使用。本研究的目的是开发一个描述健康受试者和药物敏感或耐多药结核病患者在 I 期和 II 期研究中浓度-时间数据的 bedaquiline 人口药代动力学 (PK) 模型。总共使用了来自 480 名受试者的 5,222 个 PK 观测值进行非线性混合效应建模方法。PK 用一个具有双重零阶输入（以捕捉吸收期间观察到的双重峰）和长末端半衰期（t1/2）的四室处置模型来描述。该模型包括受试者之间在表观清除率 (CL/F)、表观中央分布体积 (Vc/F)、第一次输入的剂量比例和生物利用度 (F) 上的变异性。Bedaquiline 广泛分布，稳态时表观体积超过 10,000 升，清除率低。长末端 t1/2 可能是由于从组织室重新分布。最终的协变量模型充分描述了数据，并且具有良好的模拟特征。CL/F 发现黑种人受试者比其他种族的受试者高 52.0%，女性的 Vc/F 比男性低 15.7%，尽管它们对 bedaquiline 暴露的影响被认为在临床上不相关。研究之间在 F 和 CL/F 上观察到小的差异。未解释的残留变异性为 20.6%，长期 II 期研究的变异性更高（27.7%）。
Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and Vc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
Bedaquiline在大鼠中会分布到乳汁中；目前尚不清楚该药物是否也会分布到人类乳汁中。
Bedaquiline is distributed into milk in rats; it is not known whether the drug is distributed into human milk.
generation via deprotonation at the gamma-position of 4, followed by regio- and enantioselective protonation at the alpha-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu(4)NCl markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization
[EN] SUBSTITUTED DERIVATIVE OF OXYPHOSPHORUS ACIDS, ITS USE AND PHARMACEUTICAL PREPARATION CONTAINING IT<br/>[FR] DÉRIVÉ SUBSTITUÉ D'ACIDES D'OXYPHOSPHORE, SON UTILISATION ET PRÉPARATION PHARMACEUTIQUE LE CONTENANT
申请人：UNIV KARLOVA
公开号：WO2016095878A1
公开（公告）日：2016-06-23
Antitubercular active compounds based on oxyphosphorus acids derivatives of substituted salicylanilides of general formula I, wherein each R1, R2 is independently H, halogen, or NO2; each R3, R4 is independently H, halogen, NO2, or CF3; R5 is H, halogen, or NO2; R6 is C2- C16alkyl, C6-C18aryl, C6-C18aryloxy, or C6-C18arylC2-C16alkyloxy; R7 is C6-C18aryl, C6- C18aryloxy, C6-C18aryl C2-C16alkyloxy, or R7 is missing; R8 is H or single bond to phosphorus atom. These compounds can be obtained by simple synthetic procedures and they show high in vitro antimycobacterial activity including multidrug-resistant strains. The invention provides also the use of these compounds as antitubercular and/or antimycobacterial drugs as well as a pharmaceutical preparation containing as an active substance compound of general formula I.
