Delving into the Latest Updates on Laromustine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Cloretazine, Laromustine (USAN), Onrigin

+ [6]

Target

DNA

Action

inhibitors

Mechanism

DNA inhibitors(DNA inhibitors), DNA alkylating agents

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesRespiratory Diseases+ [4]

Active Indication-

Inactive Indication

acute leukemiaAcute Myeloid LeukemiaAcute Promyelocytic Leukemia+ [13]

Originator Organization

Nanotherapeutics, Inc.

Active Organization-

Inactive Organization

Vion Pharmaceuticals, Inc.

Viron Therapeutics, Inc.

Nanotherapeutics, Inc.

License Organization-

Drug Highest PhaseSuspendedPhase 3

First Approval Date-

RegulationOrphan Drug (United States)

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Structure/Sequence

Molecular FormulaC6H14ClN3O5S2

InChIKeyPVCULFYROUOVGJ-UHFFFAOYSA-N

CAS Registry173424-77-6

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.

Start Date01 Jan 2009

Sponsor / Collaborator

Institut Jean Paoli & Irene Calmettes

NL-OMON26145

/ SuspendedNot ApplicableIIT

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)

Start Date01 Oct 2008

Sponsor / Collaborator-

100 Clinical Results associated with Laromustine

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100 Translational Medicine associated with Laromustine

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100 Patents (Medical) associated with Laromustine

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72

Literatures (Medical) associated with Laromustine

01 Mar 2019·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

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

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.

01 Nov 2018·Drug metabolism and disposition: the biological fate of chemicalsQ2 · MEDICINE

Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds

Q2 · MEDICINE

Article

Author: Obach, R Scott ; Berellini, Giuliano ; Lombardo, Franco

We report a trend analysis of human intravenous pharmacokinetic data on a data set of 1352 drugs. The aim in building this data set and its detailed analysis was to provide, as in the previous case published in 2008, an extended, robust, and accurate resource that could be applied by drug metabolism, clinical pharmacology, and medicinal chemistry scientists to a variety of scaling approaches. All in vivo data were obtained or derived from original references, either through the literature or regulatory agency reports, exclusively from studies utilizing intravenous administration. Plasma protein binding data were collected from other available sources to supplement these pharmacokinetic data. These parameters were analyzed concurrently with a range of physicochemical properties, and resultant trends and patterns within the data are presented. In addition, the date of first disclosure of each molecule was reported and the potential "temporal" impact on data trends was analyzed. The findings reported here are consistent with earlier described trends between pharmacokinetic behavior and physicochemical properties. Furthermore, the availability of a large data set of pharmacokinetic data in humans will be important to further pursue analyses of physicochemical properties, trends, and modeling efforts and should propel our deeper understanding (especially in terms of clearance) of the absorption, distribution, metabolism, and excretion behavior of drug compounds.

04 May 2017·Xenobiotica; the fate of foreign compounds in biological systemsQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: 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 Deals associated with Laromustine

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External Link

KEGG	Wiki	ATC	Drug Bank
D08939	-	-	DB05817

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 3	United Kingdom	Vion Pharmaceuticals, Inc.	18 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	United States	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	Belgium	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	Canada	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	France	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	Germany	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	Greece	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	Netherlands	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	Poland	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	Serbia	Vion Pharmaceuticals, Inc.	01 Mar 2005

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00112554 (Pubmed \| Blood)	Phase 3	Relapsing acute myeloid leukemia	-	Laromustine and high-dose cytarabine (HDAC)	waihcjcfrk(tfemgodfsa) = sthcdpxcvn qxbrvxcxyg (xpnxirzfej ) View more	-	05 Nov 2009
NCT00112554 (Pubmed \| Blood)	Phase 3	Relapsing acute myeloid leukemia	-	HDAC/placebo	waihcjcfrk(tfemgodfsa) = boqxqesnqh qxbrvxcxyg (xpnxirzfej ) View more	-	05 Nov 2009
ASCO2009	Phase 1	Acute Myeloid Leukemia \| Myelodysplastic Syndromes	-	Laromustine 300 mg/m2	lsxcivcryi(emosigkint) = cizwfchqfg shktvhqzml (trevcbmefz )	-	20 May 2009
ASCO2008	Phase 2	Acute Myeloid Leukemia	85	VNP40101M	nwecwaqosb(zgkrlywqcs) = 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. rgxftgkxat (ypsqkednwc )	-	20 May 2008
ASCO2008	Phase 3	Relapsing acute myeloid leukemia	420	araC + 101M	dzqixoqfce(erlwszxwbg) = rulxuotikj aufdajlfgr (psbsmcyetz ) View more	-	20 May 2008
ASCO2008	Phase 3	Relapsing acute myeloid leukemia	420	araC + placebo	dzqixoqfce(erlwszxwbg) = nkgwfahyol aufdajlfgr (psbsmcyetz ) View more	-	20 May 2008
Pubmed \| Clin Cancer Res	Phase 1	Brain Cancer	42	VNP40101M (Cloretazine)	xrzuenmupl(sqqloacjbi) = zdiopkqtfb ebyuljteov (pdbfmiediw ) View more	-	15 Feb 2008
ASCO2007	Phase 1	Brain Cancer	41	VNP40101M	nwypsayujy(nxmfmoofbe) = 1 case mnssodajwf (wxfifvppfl ) View more	-	20 Jun 2007
Pubmed \| J Clin Oncol	Phase 2	Acute Myeloid Leukemia	-	Cloretazine 600 mg/m2	xrzxzyxwxp(qdfjlmwetn) = vbanebnjpk xhytfqvqcx (vhxpnbcbjk ) View more	-	01 Jan 2007
ASCO2006	Not Applicable	Acute Myeloid Leukemia	105	Cloretazine	jbdqmlghfe(zvjvzqskgr) = tmnrrfwrpa cgpvrozedk (lpbvpnekju ) View more	Positive	20 Jun 2006
ASCO2006	Phase 2	Acute Myeloid Leukemia \| Myelodysplastic Syndromes	105	Cloretazine	zshiaigwyj(vioqjplzgm) = zxavuwqohy cxazciazrc (ewwlqiwkmt )	-	20 Jun 2006
ASCO2005	Phase 1/2	Hematologic Neoplasms	-	VNP40101M	itxelqidqj(pqdsmczqtw) = zkttpjjwwg pgqzkwmlzy (rpdwknptra )	-	01 Jun 2005
ASCO2005	Phase 1/2	Hematologic Neoplasms	-	araC	itxelqidqj(pqdsmczqtw) = ywvmhmlanx pgqzkwmlzy (rpdwknptra )	-	01 Jun 2005