Phase I and Pharmacokinetics Study to Determine the Safety of BIBX 1382 in Patients With a Solid Tumor on a Continuous Daily Oral Administration Schedule and After Single Oral and Intravenous Doses

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: Phase I trial to study the effectiveness of BIBX 1382 in treating patients who have solid tumors.

开始日期1999-02-01

申办/合作机构

Eortc

100 项与氟尼达莫相关的临床结果

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100 项与氟尼达莫相关的转化医学

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100 项与氟尼达莫相关的专利（医药）

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项与氟尼达莫相关的文献（医药）

2023-10-01·Drug Metabolism and Disposition

Dissecting Parameters Contributing to the Underprediction of Aldehyde Oxidase-Mediated Metabolic Clearance of Drugs

Article

作者: Kulkarni, Priyanka ; Murray, Bernard P ; Prasad, Bhagwat ; Subash, Sandhya ; Smith, Bill J ; Ahire, Deepak S ; Singh, Dilip K ; Jones, Robert S ; Cronin, Ciarán N ; Zientek, Michael A ; Heyward, Scott ; Khojasteh, S Cyrus

We investigated the effect of variability and instability in aldehyde oxidase (AO) content and activity on the scaling of in vitro metabolism data. AO content and activity in human liver cytosol (HLC) and five recombinant human AO preparations (rAO) were determined using targeted proteomics and carbazeran oxidation assay, respectively. AO content was highly variable as indicated by the relative expression factor (REF; i.e., HLC to rAO content) ranging from 0.001 to 1.7 across different in vitro systems. The activity of AO in HLC degrades at a 10-fold higher rate in the presence of the substrate as compared with the activity performed after preincubation without substrate. To scale the metabolic activity from rAO to HLC, a protein-normalized activity factor (pnAF) was proposed wherein the activity was corrected by AO content, which revealed up to sixfold higher AO activity in HLC versus rAO systems. A similar value of pnAF was observed for another substrate, ripasudil. Physiologically based pharmacokinetic (PBPK) modeling revealed a significant additional clearance (CL; 66%), which allowed for the successful prediction of in vivo CL of four other substrates, i.e., O-benzyl guanine, BIBX1382, zaleplon, and zoniporide. For carbazeran, the metabolite identification study showed that the direct glucuronidation may be contributing to around 12% elimination. Taken together, this study identified differential protein content, instability of in vitro activity, role of additional AO clearance, and unaccounted metabolic pathways as plausible reasons for the underprediction of AO-mediated drug metabolism. Consideration of these factors and integration of REF and pnAF in PBPK models will allow better prediction of AO metabolism. SIGNIFICANCE STATEMENT: This study elucidated the plausible reasons for the underprediction of aldehyde oxidase (AO)-mediated drug metabolism and provided recommendations to address them. It demonstrated that integrating protein content and activity differences and accounting for the loss of AO activity, as well as consideration of extrahepatic clearance and additional pathways, would improve the in vitro to in vivo extrapolation of AO-mediated drug metabolism using physiologically based pharmacokinetic modeling.

2022-04-01·Free Radical Biology and Medicine2区 · 医学

Falnidamol and cisplatin combinational treatment inhibits non-small cell lung cancer (NSCLC) by targeting DUSP26-mediated signal pathways

2区 · 医学

Article

作者: Zhao, Jun ; Chen, Kai ; Cui, Zihan ; Li, Dapeng

Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers worldwide with limited effective therapies. Cisplatin (DDP), as the first-line treatment, is always served as a mainstay of chemotherapeutic agents in combination with other drugs for NSCLC treatment. Nevertheless, DDP-based therapy is limited due to the frequent development of chemoresistance and adverse effects. Herein, it is necessary to find a more effective therapeutic approach with less toxicity. Falnidamol (FLD) is a pyrimido-pyrimidine compound and exerts anti-cancer activity. In the present study, we found that FLD could strongly promote the cytotoxicity of DDP and markedly reduce the IC₅₀ values to restrain the proliferation of NSCLC cells. Furthermore, combination of FLD and DDP remarkably induced G2/M cell cycle arrest, DNA damage and mitochondrial apoptosis, which was largely through the induction of reactive oxygen species (ROS). Additionally, FLD/DDP in combination greatly triggered ferroptosis, along with free iron accumulation and enhanced lipid peroxidation. Epithelial to mesenchymal transition (EMT) and epidermal growth factor receptor (EGFR) phosphorylation were also considerably restrained in NSCLC cells co-treated with FLD/DDP. Mechanistically, the combinative treatment significantly reduced DUSP26 expression in NSCLC cells. More studies showed that DUSP26 was strongly up-regulated in human NSCLC samples compared with the paired normal tissues, and high DUSP26 predicted poor overall survival rate among patients. Importantly, we found that DUSP26 suppression intensively reduced the proliferation, EMT process and pEGFR expression in NSCLC cells, whereas facilitated ROS production, DNA damage and cell death; however, opposite phenotype was observed in NSCLC cells over-expressing DUSP26. More importantly, DUSP26 over-expression completely abolished the anti-cancer function of FLD/DDP in NSCLC cells. Animal studies finally confirmed that FLD/DDP in combination efficiently reduced tumor growth and lung metastasis in mice with ameliorated side effects. In conclusion, all these data illustrated that FLD and DDP combinational treatment effectively restrained NSCLC progression, and thus can be served as a promising therapeutic strategy.

2021-12-01·Drug Metabolism and Pharmacokinetics4区 · 医学

Oxidative metabolism and pharmacokinetics of the EGFR inhibitor BIBX1382 in chimeric NOG-TKm30 mice transplanted with human hepatocytes

4区 · 医学

Article

作者: Yamazaki, Hiroshi ; Higuchi, Yuichiro ; Yoneda, Nao ; Uehara, Shotaro ; Suemizu, Hiroshi

The epidermal growth factor receptor inhibitor BIBX1382 has failed in drug development because of poor oral exposure and low bioavailability associated with its extensive metabolism by aldehyde oxidase (AOX) in humans. In this study, we investigated the metabolic profiles and pharmacokinetics of BIBX1382 in chimeric NOG-TKm30 mice with humanized liver (humanized liver mice). After intravenous and oral BIBX1382 administration, increased plasma clearance and decreased oral exposure together with high production of the predominant oxidative metabolite (M1, BIBU1476) and secondary oxidized metabolite (M2) were observed in humanized liver mice. Extensive oxidation rates of BIBX1382 were observed in hepatocytes from humanized liver mice and were suppressed by the typical human AOX1 inhibitors raloxifene and hydralazine. Liver cytosolic fractions from humans, humanized liver mice, cynomolgus monkeys, minipigs, and guinea pigs, but not fractions from dogs, rabbits, rats, and mice, displayed high BIBX1382 clearance and resulted in oxidative metabolite production. These results indicate that humanized liver mice have human-type AOX activity based on the transplanted human liver AOX1 function. Humanized liver mice can be considered an important animal model for understanding the metabolism and pharmacokinetics of AOX drug substrates.

100 项与氟尼达莫相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12966

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	临床1期	瑞士	Eortc	1999-02-01
实体瘤	临床1期	挪威	Eortc	1999-02-01
实体瘤	临床1期	德国	Eortc	1999-02-01
实体瘤	临床1期	奥地利	Eortc	1999-02-01
实体瘤	临床1期	荷兰	Eortc	1999-02-01
实体瘤	临床1期	法国	Eortc	1999-02-01
实体瘤	临床1期	英国	Eortc	1999-02-01
实体瘤	临床1期	比利时	Eortc	1999-02-01
淋巴瘤	临床1期	-	C.H. Boehringer Sohn AG & Co. KG	-
肿瘤	临床1期	德国	Boehringer Ingelheim GmbH	-