更新于：2024-05-01
Contezolid Acefosamil
更新于：2024-05-01
概要
基本信息
药物类型 小分子化药 |
别名 Contezolid acefosamil (USAN)、MRX-4-MICURX、MRX-IV + [2] |
作用机制 50S subunit抑制剂(50S核糖体亚基抑制剂)、蛋白质生物合成抑制剂 |
在研适应症 |
非在研适应症 |
非在研机构- |
最高研发阶段临床3期 |
首次获批日期- |
最高研发阶段(中国)临床3期 |
特殊审评快速通道 (美国)、合格传染病产品 (美国) |
结构
分子式C20H18F3N4O8P |
InChIKeyYCRAGJLWFBGKFE-CYBMUJFWSA-N |
CAS号1807497-11-5 |
查看全部结构式(2)
关联
5
项与 Contezolid Acefosamil 相关的临床试验A Phase 3, Multicenter, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Contezolid Acefosamil and Contezolid Compared to Linezolid Administered Intravenously and Orally to Adults With Moderate or Severe Diabetic Foot Infections (DFI)
考察健康中国受试者静脉输注和口服MRX-4后的安全性和药代动力学特征的随机、双盲、安慰剂对照的I期临床试验
A Phase 2, Multicenter, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Contezolid Acefosamil Compared to Linezolid Administered Intravenously and Orally to Adult Subjects With Acute Bacterial Skin and Skin Structure Infection
100 项与 Contezolid Acefosamil 相关的临床结果
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100 项与 Contezolid Acefosamil 相关的转化医学
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100 项与 Contezolid Acefosamil 相关的专利（医药）
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4
项与 Contezolid Acefosamil 相关的文献（医药）2024-01-18Journal of applied toxicology : JAT
Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs.
Article
作者: Wen Wang ; Zhengyao Li ; Mikhail F Gordeev ; Hong Yuan
Contezolid acefosamil (CZA) is an intravenous prodrug of oxazolidinone antibiotic contezolid (CZD). It is being developed to treat infections due to Gram-positive bacteria including multidrug-resistant pathogens, while addressing myelosuppression and neurotoxicity limitations associated with long-term use of this class of antibiotics. In vivo, CZA is rapidly deacylated into its first metabolite MRX-1352, which is then dephosphorylated to release active drug CZD. Four-week repeat-dose toxicity studies of intravenous CZA were conducted in Sprague-Dawley rats (40, 80, and 160/120 mg/kg/dose twice a day [BID]) and beagle dogs (25, 50, and 100/75 mg/kg/dose BID). The high doses administered to both rats and dogs were adjusted due to adverse effects including decreased body weight and food consumption. Additionally, a dose-dependent transient reduction in erythrocyte levels was recorded at the end of dosing phase. Importantly, no myelosuppressive reduction in platelet counts was observed, in contrast to the myelosuppression documented for standard-of-care oxazolidinone linezolid. The no-observed-adverse-effect level (NOAEL) of CZA was 80 and 25 mg/kg/dose BID in rats and dogs, respectively. Separately, 3-month neuropathological evaluation in Long-Evans rats (25, 37.5, and 50 mg/kg/dose, oral CZA, BID) demonstrated no neurotoxicity in the central, peripheral, and optical neurological systems. Toxicokinetic data from these studies revealed that CZD exposures at NOAELs were higher than or comparable with that for the intended clinical dose. These results confirm the favorable safety profile for CZA and support its clinical evaluation for long-term therapy of persistent Gram-positive infections, beyond the application for earlier oxazolidinones.
2023-10-30Antimicrobial agents and chemotherapy
A phase I study of the safety, tolerability, and pharmacokinetics of contezolid acefosamil after intravenous and oral administration in healthy Chinese subjects.
Article
作者: Haijing Yang ; Yi Jin ; Hailin Wang ; Hong Yuan ; Jingjing Wang ; Size Li ; Yingying Hu ; Huahui Yang ; Xin Li ; Hong Liang ; Jufang Wu ; Guoying Cao ; Jing Zhang
Contezolid acefosamil (also known as MRX-4), a prodrug of contezolid, is under development for treatment of multidrug-resistant Gram-positive bacterial infections. A phase I single ascending dose (SAD) and multiple-dose placebo-controlled study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of contezolid acefosamil in healthy Chinese subjects following intravenous (IV) and oral administration. Adverse events (AEs) and PK parameters were assessed appropriately. All subjects (n = 70) completed the trial. Overall, 67 cases of treatment-emergent adverse events (TEAEs) were observed in 49.1% (27 of 55) of the subjects receiving contezolid acefosamil. All TEAEs were mild in severity. No serious AEs or deaths were reported. After IV SAD (500-2,000 mg), the corresponding Cmax of the active drug contezolid increased from 1.95 ± 0.57 to 15.61 ± 4.88 mg/L, AUC0-inf from 40.25 ± 10.12 to 129.41 ± 38.30 h·mg/L, median Tmax from 2.00 to 2.75 h, and mean t1/2 from 13.33 to 16.74 h. Plasma contezolid reached steady state on day 6 after multiple IV doses, with an accumulation ratio of 2.20-2.96. Oral SAD of 500 and 1,500 mg resulted in contezolid Cmax of 8.66 ± 2.60 and 37.10 ± 8.66 mg/L, AUC0-inf of 30.44 ± 7.33 and 162.36 ± 47.08 h·mg/L, and median Tmax of 2.50 and 2.98 h. Contezolid reached steady state on day 5 after multiple oral doses of 1,500 mg without significant accumulation. Contezolid Cmax and AUC0-inf increased with the dose of contezolid acefosamil. The good safety and PK profiles in this SAD and multiple-dose study can support further clinical development of contezolid acefosamil.
2022-07-14ACS medicinal chemistry letters
Discovery of Antibacterial Contezolid Acefosamil: Innovative O-Acyl Phosphoramidate Prodrug for IV and Oral Therapies.
Article
作者: Jinqian Liu ; Wen Wang ; Changqing Wang ; Li Zhang ; Xueliang Zhang ; Shicong Liu ; Yunhua Xu ; Hailin Wang ; Qing Dai ; Chun Liu ; Xinghai Wang ; Zhengyu Yuan ; Mikhail F Gordeev
New oral antibiotic contezolid (CZD) is effective against Gram-positive infections but unsuitable for intravenous (IV) administration due to its modest solubility. To address the medical need for an IV form of CZD, its isoxazol-3-yl phosphoramidate derivatives have been explored, and contezolid acefosamil (CZA, 8), the first representative of a novel O-acyl phosphoramidate prodrug class, has been identified. CZA exhibits high aqueous solubility (>200 mg/mL) and good hydrolytic stability at media pH suitable for IV administration. CZA rapidly converts into the active drug CZD in vivo. In a pharmacokinetic (PK) rat model, the exposure of active drug CZD after IV administration of the prodrug CZA was similar to or higher than that from the IV administration of CZD. The prodrug CZA is bioequivalent to or better than CZD in several preclinical infection models. CZA is likewise active upon its oral administration. To date, CZA has been evaluated in Phase 1 and Phase 2 clinical trials in the USA. It is advancing into further clinical studies including step-down therapy with in-hospital intravenous CZA administration followed by outpatient oral CZD treatment.
16
项与 Contezolid Acefosamil 相关的新闻（医药）2024-02-13
·医药观澜
快速通道临床1期临床3期抗体药物偶联物
2023-11-27
·信狐药迅
2023-11-24
·美通社
临床3期上市批准申请上市
100 项与 Contezolid Acefosamil 相关的药物交易
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研发状态
| 适应症 | 最高研发状态 | 国家/地区 | 公司 |
|---|---|---|---|
| 糖尿病足感染 | 临床3期 | 美国 更多 | |
| 复杂的皮肤和软组织感染 | 临床3期 | 中国 更多 | |
| 皮肤和皮肤结构感染 | 临床3期 | 全球 更多 | |
| 粪肠球菌感染 | 临床申请批准 | 中国 更多 | |
| 革兰氏阳性细菌感染 | 临床申请批准 | 中国 更多 |
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临床结果
临床结果
适应症
分期
评价
查看全部结果
临床2期 | 196 | (Contezolid Acefosamil) | (鑰網醖齋憲範壓積築蓋): Median Difference (Net) = -0.6 (95% CI, -14.0 ~ 2.8) | - | 2021-04-30 | ||
(Linezolid) |
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