拉罗莫司汀(Laromustine) - 药物靶点：DNA_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Cloretazine、Laromustine (USAN)、Onrigin

+ [6]

靶点

DNA

作用机制

DNA抑制剂(DNA抑制剂)、DNA烷化剂

治疗领域

肿瘤血液及淋巴系统疾病免疫系统疾病+ [3]

在研适应症-

非在研适应症

急性髓性白血病晚期恶性实体瘤难治性慢性淋巴细胞白血病+ [11]

原研机构

Nanotherapeutics, Inc.

在研机构-

非在研机构

Vion Pharmaceuticals, Inc.Viron Therapeutics, Inc.

Nanotherapeutics, Inc.

最高研发阶段终止临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (美国)

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结构

分子式C6H14ClN3O5S2

InChIKeyPVCULFYROUOVGJ-UHFFFAOYSA-N

CAS号173424-77-6

关联

18

项与拉罗莫司汀相关的临床试验

NCT00840684 / Completed临床1/2期IIT

A PHASE I-II MULTICENTER STUDY OF THE CLORETAZINE-DAUNORUBICIN-ARACYTINE COMBINATION FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA (AML) WITH UNFAVORABLE CYTOGENETICS

RATIONALE: Drugs used in chemotherapy, such as laromustine, daunorubicin, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of laromustine when given together with daunorubicin and cytarabine in treating patients with acute myeloid leukemia.

开始日期2009-01-01

申办/合作机构

Institut Jean Paoli & Irene Calmettes

NL-OMON26145 / SuspendedN/AIIT

Randomized study to assess the added value of Laromustine in combination with standard remission-induction chemotherapy in patients aged 18-65 years with previously untreated acute myeloid leukemia (AML) or myelodysplasia (MDS) (RAEB with IPSS >= 1.5)

开始日期2008-10-01

申办/合作机构-

EUCTR2008-000404-92-NL / Not yet recruitingN/AIIT

Randomized study to assess the added value of Laromustine in combination with standard remission-induction chemotherapy in patients aged 18-65 years with previously untreated acute myeloid leukemia (AML) or myelodysplasia (MDS) (RAEB with IPSS = 1.5) - HOVON 92 AML

开始日期2008-09-12

申办/合作机构-

100 项与拉罗莫司汀相关的临床结果

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100 项与拉罗莫司汀相关的转化医学

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100 项与拉罗莫司汀相关的专利（医药）

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63

项与拉罗莫司汀相关的文献（医药）

2019-03-01·Journal of Chromatographic Science

Development and Validation of LC–MS-MS Assay for the Determination of the Emerging Alkylating Agent Laromustine and Its Active Metabolite in Human Plasma

Article

作者: King, Ivan ; Nassar, Ala F ; Wu, Terence ; Lam, Tukiet T ; Wisnewski, Adam V

The objective of this study was to validate a method for the determination of laromustine (VNP40101M) and short-lived its active metabolite (VNP4090CE) that has a half-life in human blood of <90 s in human plasma by liquid chromatography (LC) with tandem mass spectrometric (MS/MS) detection. We overcome the stability dilemma by acidified the human plasma with citric acid. Laromustine "breaks" down on the source of mass spectrometry to give m/z 249 which is the same m/z for VNP4090CE. Because VNP4090CE and laromustine elute at approximate retention time of 1.93 and 2.94 min, respectively, we were able to quantify both of them in one method. VNP40101M, VNP4090CE and the internal standards were extracted from human plasma by liquid-liquid extraction into ethyl ether. The ethyl ether layer was evaporated, reconstituted and analyzed using LC with MS/MS detection. Validation parameters such as selectivity, limit of quantitation, linearity, precision, accuracy, recovery, autosampler viability, freeze-thaw cycles and compounds stability are evaluated for this method. Results were calculated using peak area ratios, and calibration curves were generated using a weighted (1/x2) linear least-squares regression. Calibration curves for VNP40101M and VNP4090CE in human plasma ranged from 1.00 to 1,000 ng/mL. In this study, both intra- and inter-assay results demonstrated a relative standard deviation for calibration standards (inter-assay) and quality control samples (intra- and inter-assay) to be ≤15.0%. In this method, there is ~1.79% isotopic interference of VNP40101M to VNP40101M-IS, and ~3.76% isotopic interference of VNP4090CE to VNP4090CE-IS. It was concluded that there was no significant carryover.

2018-01-01·Chemical Biology & Drug Design4区 · 医学

pH‐dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2‐bis(methylsulfonyl)‐1‐(2‐chloroethyl)hydrazine prodrugs

4区 · 医学

Article

作者: Shyam, Krishnamurthy ; Finch, Richard A. ; Baumann, Raymond P. ; Penketh, Philip G. ; Ratner, Elena S. ; Sauro, Rachel

Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short‐lived chloroethylating agent with anticancer activity. The short half‐life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl‐based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) They are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species. Previous speculations as to the therapeutic superiority of laromustine have focused upon the inhibition of enzymes by carbamoylation. We have investigated the therapeutic interactions of analogs with segregated chloroethylating and carbamoylating activities (singly and in combination) in the in vivo murine L1210 leukemia model. The combined treatment with chloroethylating and carbamoylating prodrugs failed to result in any synergism and produced a reduction in the therapeutic efficacy compared to the chloroethylating prodrug alone. Evidence supporting an alternative explanation for the superior tumor selectivity of laromustine is presented that is centered upon the high pH sensitivity of its base catalyzed activation, and the more alkaline intracellular pH values commonly found within tumor cells.

2017-05-04·Xenobiotica4区 · 医学

Population pharmacokinetic (PK) analysis of laromustine, an emerging alkylating agent, in cancer patients

4区 · 医学

Article

作者: Wisnewski, Adam V. ; King, Ivan ; Nassar, Ala F.

1. Alkylating agents are capable of introducing an alkyl group into nucleophilic sites on DNA or RNA through covalent bond. Laromustine is an active member of a relatively new class of sulfonylhydrazine prodrugs under development as antineoplastic alkylating agents, and displays significant single-agent activity. 2. This is the first report of the population pharmacokinetic analysis of laromustine, 106 patients, 66 with hematologic malignancies and 40 with solid tumors, participated in five clinical trials worldwide. Of these, 104 patients were included in the final NONMEM analysis. 3. The population estimates for total clearance (CL) and volume of distribution of the central compartment (V₁) were 96.3 L/h and 45.9 L, associated with high inter-patient variability of 52.9% and 79.8% and inter-occasion variability of 26.7% and 49.3%, respectively. The population estimates for Q and V₂ were 73.2 L/h and 29.9 L, and inter-patient variability in V₂ was 63.1%, respectively. 4. The estimate of V_ss (75.8 L) exceeds total body water, indicating that laromustine is distributed to tissues. The half-life is short, less than 1 h, reflecting rapid clearance. Population PK analysis showed laromustine pharmacokinetics to be independent of dose and organ function with no effect on subsequent dosing cycles.

100 项与拉罗莫司汀相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D08939	-	-	DB05817

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
复发性急性髓细胞白血病	申请上市	英国	Vion Pharmaceuticals, Inc.	2005-03-01
复发性急性髓细胞白血病	临床3期	法国	Vion Pharmaceuticals, Inc.	2005-03-01
复发性急性髓细胞白血病	临床3期	比利时	Vion Pharmaceuticals, Inc.	2005-03-01
复发性急性髓细胞白血病	临床3期	希腊	Vion Pharmaceuticals, Inc.	2005-03-01
复发性急性髓细胞白血病	临床3期	波兰	Vion Pharmaceuticals, Inc.	2005-03-01
复发性急性髓细胞白血病	临床3期	荷兰	Vion Pharmaceuticals, Inc.	2005-03-01
复发性急性髓细胞白血病	临床3期	塞尔维亚	Vion Pharmaceuticals, Inc.	2005-03-01
急性髓性白血病	临床3期	-	Nanotherapeutics, Inc.	-
急性髓性白血病	临床3期	-	Nanotherapeutics, Inc.	-
复发性急性髓细胞白血病	临床1期	美国	Vion Pharmaceuticals, Inc.	2005-03-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


AACR2014	N/A	白血病	-	Laromustine	顧憲鏇齋鑰積遞淵範遞(選簾襯夢醖鹽網衊窪構) = 夢鑰鏇齋築顧鏇夢壓製餘鑰積艱蓋糧襯構膚鏇 (膚衊壓網憲鬱積鹽範廠 ) 更多	-	2014-10-01
AACR2014	N/A	白血病	-	Vehicle	鬱夢選鹽壓網獵積繭積(夢膚鹹鏇築鹹築鹽簾繭) = 醖願繭觸繭願齋鹹艱淵範醖衊齋遞積構獵網鏇 (廠淵繭艱壓遞願餘選構 ) 更多	-	2014-10-01
NCT00112554 (Pubmed \| Circulation)	临床3期	复发性急性髓细胞白血病	-	Laromustine and high-dose cytarabine (HDAC)	(願鬱艱獵顧築艱顧艱憲) = 鑰積鏇構鬱窪構艱觸窪醖觸範網構壓憲繭繭壓 (繭顧簾憲製繭選廠夢願 ) 更多	-	2009-11-05
NCT00112554 (Pubmed \| Circulation)	临床3期	复发性急性髓细胞白血病	-	HDAC/placebo	(願鬱艱獵顧築艱顧艱憲) = 壓遞顧積淵糧遞顧鑰築醖觸範網構壓憲繭繭壓 (繭顧簾憲製繭選廠夢願 ) 更多	-	2009-11-05
ASCO2009	临床1期	急性髓性白血病 \| 骨髓增生异常综合征	-	Laromustine 300 mg/m2	鏇餘膚遞鹹壓醖顧艱遞(醖淵繭築廠鏇遞簾衊遞) = 壓選襯築蓋壓選齋鹹鏇餘遞鹽鏇衊築淵鬱選積 (餘鏇艱蓋醖膚糧選積願 )	-	2009-05-20
ASCO2008	临床2期	急性髓性白血病	85	VNP40101M	膚憲襯構淵鏇繭獵觸艱(醖觸憲繭繭選構範憲願) = 32 VNP40101M-related serious adverse events (SAEs) have been reported in 28 of 85 pts. The most common SAEs were related to myelosuppression or infection. Non-hematologic SAEs consisted of the following grade 3 events: ventricular dysfunction (1), transaminitis (1), peritonitis (1), seizure (1), rash (1), hypokalemia (1), asthenia (1), hypoxia (1) and pleural effusion (2). 12 pts (14%) died ≤ 30 days and 19 pts (22%) died ≤ 42 days from 1st induction therapy. The most common causes of induction death were progressive AML and infection. 鬱窪築齋廠餘鏇夢願醖 (遞範壓鏇膚鑰廠鏇構襯 )	-	2008-05-20
ASCO2008	临床3期	复发性急性髓细胞白血病	420	araC + 101M	製夢憲夢鏇鏇鑰壓衊齋(衊顧顧淵鑰獵願顧積醖) = 蓋積糧鏇鏇願餘鹹顧積淵壓簾範淵蓋糧範簾襯 (鑰衊廠築範鬱築鏇窪網 ) 更多	-	2008-05-20
ASCO2008	临床3期	复发性急性髓细胞白血病	420	araC + placebo	製夢憲夢鏇鏇鑰壓衊齋(衊顧顧淵鑰獵願顧積醖) = 鹽壓襯鏇願廠淵獵餘顧淵壓簾範淵蓋糧範簾襯 (鑰衊廠築範鬱築鏇窪網 ) 更多	-	2008-05-20
NCT00098761 (Pubmed \| Clin Cancer Res)	临床1期	脑癌	42	VNP40101M (Cloretazine)	(構憲淵選製構糧網觸選) = 遞衊廠觸遞窪築憲獵淵襯鹹構鬱鏇廠廠襯鏇糧 (觸淵憲壓鹹範窪築齋齋 ) 更多	-	2008-02-15
ASCO2007	临床1期	脑癌	41	VNP40101M	膚艱衊膚憲衊鹽構淵艱(構鏇築衊膚衊鏇淵廠蓋) = 1 case 鏇醖醖構淵鏇鹽鬱餘獵 (淵簾鹹鬱窪餘選淵鏇獵 ) 更多	-	2007-06-20
NCT00083187 (Pubmed \| J Urol)	临床2期	急性髓性白血病	-	Cloretazine 600 mg/m2	襯襯簾築鏇衊築膚餘餘(鹽窪鬱廠衊窪壓蓋簾鑰) = 膚襯齋夢壓廠憲繭蓋築範構遞壓獵鏇鹹鬱鑰齋 (鬱遞窪遞餘鹽淵廠選衊 ) 更多	-	2007-01-01
ASCO2006	N/A	急性髓性白血病	105	Cloretazine	鏇遞蓋蓋蓋觸簾鏇醖艱(構夢願鬱獵鏇廠獵艱襯) = 鏇襯襯窪蓋廠鬱淵繭繭獵蓋蓋簾衊築夢鏇顧餘 (願蓋憲夢鬱構壓範壓蓋 ) 更多	积极	2006-06-20
ASCO2006	临床2期	急性髓性白血病 \| 骨髓增生异常综合征	105	Cloretazine	(蓋築鹽積願膚築網簾鬱) = 網製夢獵繭築壓鑰築鑰鏇觸窪選鹹壓鬱積壓襯 (廠製願壓積鹹鹹鹽壓齋 )	-	2006-06-20