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Pharmacokinetics of trastuzumab and its efficacy and safety in HER2-positive cancer patients. 曲妥珠单抗的药代动力学及其对 HER2 阳性癌症患者的疗效和安全性。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-23 DOI: 10.1007/s00280-024-04707-y
Xinyu Luo, Nan Wang, Yue Xing, Xinyue Gao, Yang Yu, Tong Liu, Shuai Jiang, Mei Dong

Trastuzumab is a potent targeted therapy drug for HER2-positive cancer patients. A comprehensive understanding of trastuzumab's mechanism of action, pharmacokinetic (PK) parameters, and steady-state exposure in different treatment regimens and administration routes is essential for a thorough evaluation of the drug's safety and effectiveness. Due to the distinctive pharmacokinetics, indications, and administration methods of trastuzumab, this understanding becomes crucial. Drug exposure can be assessed by measuring trastuzumab's peak concentration, trough concentration, or area under the curve through assays like enzyme-linked immunosorbent assay (ELISA) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). The dose-response (D-R) and exposure-response (E-R) relationships establish the correlation between drug dosage/exposure and the therapeutic effect and safety. Additionally, various covariates such as body weight, aspartate transaminase, and albumin levels can influence drug exposure. This review provides a comprehensive overview of trastuzumab's mechanism of action, data on steady-state concentration and PK parameters under multiple administration routes and indications, discussions on factors influencing PK parameters, and evaluations of the effectiveness and safety of E-R and D-R in diverse HER2-positive cancer patients.

曲妥珠单抗是一种针对 HER2 阳性癌症患者的强效靶向治疗药物。全面了解曲妥珠单抗的作用机制、药动学(PK)参数以及不同治疗方案和给药途径下的稳态暴露量,对于彻底评估该药物的安全性和有效性至关重要。由于曲妥珠单抗的药代动力学、适应症和给药方法各不相同,因此了解其药代动力学至关重要。药物暴露可通过酶联免疫吸附试验(ELISA)或液相色谱-串联质谱法(LC-MS/MS)等检测方法测量曲妥珠单抗的峰浓度、谷浓度或曲线下面积来评估。剂量-反应(D-R)和暴露-反应(E-R)关系确定了药物剂量/暴露与治疗效果和安全性之间的相关性。此外,体重、天冬氨酸转氨酶和白蛋白水平等各种协变量也会影响药物暴露。本综述全面概述了曲妥珠单抗的作用机制、多种给药途径和适应症下的稳态浓度和 PK 参数数据、PK 参数影响因素讨论,以及 E-R 和 D-R 在不同 HER2 阳性癌症患者中的有效性和安全性评估。
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引用次数: 0
An interactive dose optimizer based on population pharmacokinetic study to guide dosing of methotrexate in Chinese patients with osteosarcoma. 基于群体药代动力学研究的交互式剂量优化器,用于指导中国骨肉瘤患者的甲氨蝶呤用药。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-24 DOI: 10.1007/s00280-024-04708-x
Yanjie Zhang, Xiemin Qi, Xiaohui Huang, Xiaozhou Liu, Yanyu Liu, Jianzhong Rui, Qiong Yin, Sujia Wu, Guohua Zhou

Purpose: Osteosarcoma is a rare tumor with an incidence of 4.4 cases per million per year in adolescent. High-dose methotrexate (HD-MTX) is the standard first-line chemotherapeutic agent for osteosarcoma. However, its efficacy can vary significantly among individuals due to wide pharmacokinetic variability. Despite this, only a few population pharmacokinetics (popPK) models based on Chinese patients with osteosarcoma have been reported. Thus, this study aimed to develop a HD-MTX popPK model and an individual model-based dose optimizer for osteosarcoma therapy.

Method: A total of 680 MTX serum concentrations from 57 patients with osteosarcoma were measured at the end of MTX infusion and 10 h, 24 h, 48 h, and 72 h after the start of infusion. Using the first-order conditional estimation method with NONMEM, a popPK model was estimated. Goodness-of-fit plots, visual predictive checks, and bootstrap analysis were generated to evaluate the final model. A dose optimizer tool was developed based on the validated models using R Shiny. Additionally, clinical data from 12 patients with newly diagnosed osteosarcoma were collected and used as the validation set to preliminarily verify the predictive ability of the popPK model and the dose optimizer tool.

Results: Body surface area (BSA) was the most significant covariate for compartment distribution. Creatinine clearance (CrCL) and co-administration of NSAIDs were introduced as predictors for central compartmental and peripheral compartmental clearance, respectively. Co-administration of NSAIDs was associated with significantly higher MTX concentrations at 72 h (p = 0.019). The dose optimizer tool exhibited a high consistency in predicting MTX AUC compared to the actual AUC (r = 0.821, p < 0.001) in the validation set.

Conclusion: The dose optimizer tool could be used to estimate individual PK parameters, and optimize personalized MTX therapy in particular patients.

目的:骨肉瘤是一种罕见肿瘤,在青少年中的发病率为每年每百万人中4.4例。大剂量甲氨蝶呤(HD-MTX)是治疗骨肉瘤的标准一线化疗药物。然而,由于药代动力学的广泛变异性,其疗效在个体之间会有很大差异。尽管如此,基于中国骨肉瘤患者的群体药代动力学(popPK)模型却鲜有报道。因此,本研究旨在建立 HD-MTX popPK 模型和基于个体模型的骨肉瘤治疗剂量优化器:方法:在MTX输注结束时、输注开始后10小时、24小时、48小时和72小时测量了57名骨肉瘤患者的680个MTX血清浓度。利用 NONMEM 的一阶条件估计法,对 popPK 模型进行了估计。生成拟合优度图、视觉预测检查和引导分析来评估最终模型。根据验证过的模型,使用 R Shiny 开发了一个剂量优化工具。此外,还收集了 12 名新确诊骨肉瘤患者的临床数据作为验证集,以初步验证 popPK 模型和剂量优化工具的预测能力:体表面积(BSA)是影响分区分布的最重要的协变量。肌酐清除率(CrCL)和同时服用非甾体抗炎药分别是中心区室和外周区室清除率的预测因子。联合使用非甾体抗炎药与 72 小时内 MTX 浓度显著升高有关(p = 0.019)。与实际AUC相比,剂量优化工具在预测MTX AUC方面表现出较高的一致性(r = 0.821,p 结论):剂量优化工具可用于估计个体 PK 参数,并优化特定患者的个性化 MTX 治疗。
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引用次数: 0
Population pharmacokinetic and exposure-toxicity analyses of nab-paclitaxel after pegylated recombinant human granulocyte colony-stimulating factor administration in patients with metastatic breast cancer. 转移性乳腺癌患者服用聚乙二醇重组人粒细胞集落刺激因子后纳布-紫杉醇的群体药代动力学和暴露毒性分析。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-31 DOI: 10.1007/s00280-024-04702-3
Dihong Yang, Gaoqi Xu, Haiying Ding, Like Zhong, Junfeng Zhu, Xiufang Mi, Wenxiu Xin, Tianyan Zhou, Jiaqi Wang, Luo Fang

Purpose: This study aimed to establish a population pharmacokinetic (PK) model to evaluate the dynamic relationship between the concentrations of total and unbound paclitaxel, and the exposure-response analysis of albumin-bound paclitaxel (nab-paclitaxel) after pegylated recombinant human granulocyte colony-stimulating factor (PEG-G-CSF) administration in patients with metastatic breast cancer.

Methods: A total of 653 concentrations corresponding to total paclitaxel and 334 concentrations corresponding to unbound paclitaxel were analyzed in 24 subjects who randomized received a single 260 mg/m2 dose of two nab-paclitaxel formulations with a 21-35-day washout period. PEG-G-CSF was administered to all the patients in each cycle to prevent neutropenia. The exposure-response relationships were evaluated using the exposure to total, albumin-coated, and unbound paclitaxel, as well as the reduction in neutrophil count. The exposure data were analyzed using nonlinear mixed-effect modeling. A linear regression model was used to test the statistical significance of the correlation between percentage of reduction in neutrophil count and exposure.

Results: The PK characteristics of total paclitaxel were described using a three-compartment model with first-order elimination, and a mechanism-based model incorporating linear release of nab-paclitaxel and the saturated binding of unbound paclitaxel to plasma components was established. The release ratio of paclitaxel from nab-paclitaxel was estimated to be 4.60% and the maximum unbound fraction (2.76%) was reached at the end of the infusion. The study found that a longer duration of total paclitaxel concentration > 0.19 µmol/L was significantly correlated with a reduction in neutrophil count (r2 = 0.23, P = 0.00062). Specifically, a duration of > 8.6 h was a predictor of a decreased neutrophil count.

Conclusion: The decrease in neutrophils induced by nab-paclitaxel was significantly correlated with the duration above a total paclitaxel concentration of 0.19 µmol/L despite the use of PEG-G-CSF.

目的:本研究旨在建立一个群体药代动力学(PK)模型,以评估转移性乳腺癌患者服用聚乙二醇重组人粒细胞集落刺激因子(PEG-G-CSF)后总紫杉醇浓度与未结合紫杉醇浓度之间的动态关系,以及白蛋白结合型紫杉醇(nab-紫杉醇)的暴露-反应分析:方法:24 名受试者随机接受了单剂量 260 毫克/平方米的两种纳布紫杉醇制剂,并经过 21-35 天的冲洗期,共分析了 653 个紫杉醇总浓度和 334 个未结合紫杉醇浓度。在每个周期中,所有患者都服用了 PEG-G-CSF,以防止中性粒细胞减少症。利用总紫杉醇、白蛋白包裹紫杉醇和未结合紫杉醇的暴露量以及中性粒细胞计数的减少来评估暴露-反应关系。暴露数据采用非线性混合效应模型进行分析。使用线性回归模型检验了中性粒细胞计数减少百分比与暴露量之间相关性的统计学意义:结果:采用一阶消除的三室模型描述了总紫杉醇的 PK 特性,并建立了一个基于机理的模型,其中包含纳布-紫杉醇的线性释放和未结合紫杉醇与血浆成分的饱和结合。据估计,纳布-紫杉醇的紫杉醇释放率为 4.60%,输注结束时达到最大未结合部分(2.76%)。研究发现,紫杉醇总浓度> 0.19 µmol/L的持续时间越长,中性粒细胞计数就越少(r2 = 0.23,P = 0.00062)。结论:紫杉醇总浓度大于 0.19 µmol/L 与中性粒细胞数量减少有明显相关性(r2 = 0.23,P = 0.00062):结论:尽管使用了 PEG-G-CSF,纳布-紫杉醇诱导的中性粒细胞减少与紫杉醇总浓度超过 0.19 µmol/L 的持续时间显著相关。
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引用次数: 0
Continuous exposure to doxorubicin induces stem cell-like characteristics and plasticity in MDA-MB-231 breast cancer cells identified with the SORE6 reporter. 持续暴露于多柔比星可诱导 MDA-MB-231 乳腺癌细胞的干细胞样特征和可塑性,并通过 SORE6 报告器进行鉴定。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-24 DOI: 10.1007/s00280-024-04701-4
Nohemí Salinas-Jazmín, María Adriana Medina-Mondragón, Jeannie Jiménez-López, Sandra Lucia Guerrero-Rodríguez, Patricia Cuautle-Rodríguez, Marco Antonio Velasco-Velázquez

Purpose: Cancer stem cells (CSCs) account for recurrence and resistance to breast cancer drugs, rendering them a cause of mortality and therapeutic failure. In this study, we examined the effects of exposure to low concentrations of doxorubicin (Dox) on CSCs and non-CSCs from TNBC.

Methods: The effects of Dox were studied using the SORE6 reporter system. We examined the enrichment of the CSCs population, as well as the proliferation, and death of the reporter-positive fraction (GFP + cells) by flow cytometry. The resistant and stemness phenotypes were analyzed by viability and mammosphere formation assay, respectively. We identified differentially expressed and coregulated genes by RNA-seq analysis, and the correlation between gene expression and clinical outcome was evaluated by Kaplan-Mayer analysis using public databases.

Results: In MDAMB231 and Hs578t cells, we identified enriched subsets in the CSCs population after continuous exposure to low concentrations of Dox. Cells from these enriched cultures showed resistance to toxic concentrations of Dox and increased efficiency of mammosphere formation. In purified GFP + or GFP- cells, Dox increased the mammosphere-forming efficiency, promoted phenotypic switches in non-CSCs populations to a CSC-like state, reduced proliferation, and induced differential gene expression. We identified several biological processes and molecular functions that partially explain the development of doxorubicin-resistant cells and cellular plasticity. Among the genes that were regulated by Dox exposure, the expression of ITGB1, SNAI1, NOTCH4, STAT5B, RAPGEF3, LAMA2, and GNAI1 was significantly associated with poor survival, the stemness phenotype, and chemoresistance.

Conclusion: The generation of chemoresistant cells that have characteristics of CSCs, after exposure to low concentrations of Dox, involves the differential expression of genes that have a clinical impact.

目的:癌症干细胞(CSCs)是乳腺癌复发和耐药的原因之一,也是导致死亡和治疗失败的原因之一。在这项研究中,我们考察了暴露于低浓度多柔比星(Dox)对 TNBC 的癌干细胞和非癌干细胞的影响:方法:我们使用 SORE6 报告系统研究了 Dox 的影响。我们通过流式细胞术检测了CSCs群体的富集以及报告基因阳性部分(GFP +细胞)的增殖和死亡。抗性和干性表型分别通过存活率和乳球形成试验进行了分析。我们通过RNA-seq分析确定了差异表达基因和核心配对基因,并利用公共数据库通过Kaplan-Mayer分析评估了基因表达与临床结果之间的相关性:结果:在MDAMB231和Hs578t细胞中,我们发现了持续暴露于低浓度Dox后CSCs群体中的富集亚群。来自这些富集培养物的细胞表现出对毒性浓度Dox的耐受性,并提高了乳球形成的效率。在纯化的 GFP + 或 GFP- 细胞中,Dox 提高了乳腺小球形成的效率,促进了非 CSCs 群体向 CSC 样状态的表型转换,减少了增殖,并诱导了不同的基因表达。我们发现了一些生物过程和分子功能,它们部分解释了多柔比星耐药细胞的发育和细胞可塑性。在受Dox暴露调控的基因中,ITGB1、SNAI1、NOTCH4、STAT5B、RAPGEF3、LAMA2和GNAI1的表达与存活率低、干性表型和化疗耐药性显著相关:结论:暴露于低浓度Dox后,具有CSCs特征的化疗耐药细胞的生成涉及对临床有影响的基因的差异表达。
{"title":"Continuous exposure to doxorubicin induces stem cell-like characteristics and plasticity in MDA-MB-231 breast cancer cells identified with the SORE6 reporter.","authors":"Nohemí Salinas-Jazmín, María Adriana Medina-Mondragón, Jeannie Jiménez-López, Sandra Lucia Guerrero-Rodríguez, Patricia Cuautle-Rodríguez, Marco Antonio Velasco-Velázquez","doi":"10.1007/s00280-024-04701-4","DOIUrl":"10.1007/s00280-024-04701-4","url":null,"abstract":"<p><strong>Purpose: </strong>Cancer stem cells (CSCs) account for recurrence and resistance to breast cancer drugs, rendering them a cause of mortality and therapeutic failure. In this study, we examined the effects of exposure to low concentrations of doxorubicin (Dox) on CSCs and non-CSCs from TNBC.</p><p><strong>Methods: </strong>The effects of Dox were studied using the SORE6 reporter system. We examined the enrichment of the CSCs population, as well as the proliferation, and death of the reporter-positive fraction (GFP + cells) by flow cytometry. The resistant and stemness phenotypes were analyzed by viability and mammosphere formation assay, respectively. We identified differentially expressed and coregulated genes by RNA-seq analysis, and the correlation between gene expression and clinical outcome was evaluated by Kaplan-Mayer analysis using public databases.</p><p><strong>Results: </strong>In MDAMB231 and Hs578t cells, we identified enriched subsets in the CSCs population after continuous exposure to low concentrations of Dox. Cells from these enriched cultures showed resistance to toxic concentrations of Dox and increased efficiency of mammosphere formation. In purified GFP + or GFP- cells, Dox increased the mammosphere-forming efficiency, promoted phenotypic switches in non-CSCs populations to a CSC-like state, reduced proliferation, and induced differential gene expression. We identified several biological processes and molecular functions that partially explain the development of doxorubicin-resistant cells and cellular plasticity. Among the genes that were regulated by Dox exposure, the expression of ITGB1, SNAI1, NOTCH4, STAT5B, RAPGEF3, LAMA2, and GNAI1 was significantly associated with poor survival, the stemness phenotype, and chemoresistance.</p><p><strong>Conclusion: </strong>The generation of chemoresistant cells that have characteristics of CSCs, after exposure to low concentrations of Dox, involves the differential expression of genes that have a clinical impact.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"571-583"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Advancements in physiologically based pharmacokinetic modeling for fedratinib: updating dose guidance in the presence of a dual inhibitor of CYP3A4 and CYP2C19. 费拉替尼生理药代动力学建模的进展:更新CYP3A4和CYP2C19双重抑制剂情况下的剂量指导。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-07 DOI: 10.1007/s00280-024-04696-y
Ming Chang, Yizhe Chen, Ken Ogasawara, Brian James Schmidt, Lu Gaohua

Purpose: A physiologically based pharmacokinetic (PBPK) model for fedratinib was updated and revalidated to bridge a gap between the observed drug-drug interaction (DDI) of a single sub-efficacious dose in healthy participants and the potential DDI in patients with cancer at steady state. The study aimed to establish an appropriate dose for fedratinib in patients coadministered with dual CYP3A4 and CYP2C19 inhibitors, providing quantitative evidence to inform dosing guidance.

Methods: The original minimal PBPK model was developed using Simcyp® Simulator v17. The model was updated by substituting a single distribution rate (Qsac) with 2 separate rates (CLin/CLout) and transitioning to v20. Model parameter updates were further informed with 3 clinical studies, and 3 more studies served as independent validation data. The validated model was applied to simulate potential DDIs between fedratinib and a known dual inhibitor of CYP3A4 and CYP2C19 (fluconazole).

Results: Coadministration of fedratinib with fluconazole in patients was predicted to increase fedratinib exposure by < 2-fold in all simulated scenarios. For patients with cancer receiving the approved dose of fedratinib 400 mg once daily along with fluconazole 200 mg daily, the model predicted an approximate 50% increase in fedratinib exposure at steady state.

Conclusions: The updated PBPK model improved description of the observed pharmacokinetics and predicted a low risk of clinically significant DDIs between fedratinib and fluconazole. The quantitative evidence serves as a primary foundation for providing dose guidance in clinical practice for the coadministration of fedratinib with dual CYP3A4 and CYP2C19 inhibitors.

目的:对基于生理学的费拉替尼药代动力学(PBPK)模型进行了更新和重新验证,以弥补在健康参与者中观察到的单次亚有效剂量的药物相互作用(DDI)与癌症患者在稳定状态下的潜在DDI之间的差距。该研究旨在确定联合使用CYP3A4和CYP2C19双重抑制剂的患者服用非瑞替尼的适当剂量,为用药指导提供定量证据:使用 Simcyp® Simulator v17 开发了最初的最小 PBPK 模型。模型更新后,用两个独立的速率(CLin/CLout)取代了单一的分布速率(Qsac),并过渡到 v20。模型参数的更新进一步参考了 3 项临床研究,另外 3 项研究作为独立的验证数据。经过验证的模型被用于模拟非瑞替尼与一种已知的CYP3A4和CYP2C19双重抑制剂(氟康唑)之间潜在的DDI:结果:根据预测,患者在服用非瑞替尼的同时服用氟康唑会增加非瑞替尼的暴露量:更新后的PBPK模型改进了对所观察到的药代动力学的描述,并预测非瑞替尼与氟康唑之间发生临床重大DDI的风险较低。定量证据是临床实践中为非瑞替尼与CYP3A4和CYP2C19双重抑制剂联合用药提供剂量指导的主要依据。
{"title":"Advancements in physiologically based pharmacokinetic modeling for fedratinib: updating dose guidance in the presence of a dual inhibitor of CYP3A4 and CYP2C19.","authors":"Ming Chang, Yizhe Chen, Ken Ogasawara, Brian James Schmidt, Lu Gaohua","doi":"10.1007/s00280-024-04696-y","DOIUrl":"10.1007/s00280-024-04696-y","url":null,"abstract":"<p><strong>Purpose: </strong>A physiologically based pharmacokinetic (PBPK) model for fedratinib was updated and revalidated to bridge a gap between the observed drug-drug interaction (DDI) of a single sub-efficacious dose in healthy participants and the potential DDI in patients with cancer at steady state. The study aimed to establish an appropriate dose for fedratinib in patients coadministered with dual CYP3A4 and CYP2C19 inhibitors, providing quantitative evidence to inform dosing guidance.</p><p><strong>Methods: </strong>The original minimal PBPK model was developed using Simcyp<sup>®</sup> Simulator v17. The model was updated by substituting a single distribution rate (Q<sub>sac</sub>) with 2 separate rates (CL<sub>in</sub>/CL<sub>out</sub>) and transitioning to v20. Model parameter updates were further informed with 3 clinical studies, and 3 more studies served as independent validation data. The validated model was applied to simulate potential DDIs between fedratinib and a known dual inhibitor of CYP3A4 and CYP2C19 (fluconazole).</p><p><strong>Results: </strong>Coadministration of fedratinib with fluconazole in patients was predicted to increase fedratinib exposure by < 2-fold in all simulated scenarios. For patients with cancer receiving the approved dose of fedratinib 400 mg once daily along with fluconazole 200 mg daily, the model predicted an approximate 50% increase in fedratinib exposure at steady state.</p><p><strong>Conclusions: </strong>The updated PBPK model improved description of the observed pharmacokinetics and predicted a low risk of clinically significant DDIs between fedratinib and fluconazole. The quantitative evidence serves as a primary foundation for providing dose guidance in clinical practice for the coadministration of fedratinib with dual CYP3A4 and CYP2C19 inhibitors.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"549-559"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with 4hydroxycyclophosphamide formation in children with Cancer. 儿童癌症患者环磷酰胺药代动力学候选基因与 4hydroxycyclophosphamide 形成的药物基因组学关联。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-30 DOI: 10.1007/s00280-024-04703-2
Sandi L Navarro, Navin Pinto, Douglas S Hawkins, Julie R Park, Saam Dilmaghani, Christine Rimorin, Michelle Wurscher, Jeannine S McCune

Purpose: 4-hydroxycyclophosphamide (4HCY) is the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY), which is often used as first-line treatment of children with cancer. There is conflicting data regarding the relationship between CY efficacy, toxicity, and pharmacokinetics with the genes encoding proteins involved in 4HCY pharmacokinetics, specifically its formation and elimination.

Methods: We evaluated germline pharmacogenetics in children with various malignancies receiving their first CY dose. Using linear regression, we analyzed the associations between two pharmacokinetic outcomes - how fast a child cleared CY (i.e., CY clearance) and the ratio of the 4HCY/CY exposure, specifically area under the plasma concentration-time curve (AUC), and 372 single nucleotide polymorphisms (SNP) in 14 drug-metabolizing transporters or enzymes involved in 4HCY formation or elimination.

Results: Age was associated with the ratio of 4HCY/CY AUC (P = 0.004); Chemotherapy regimen was associated with CY clearance (P = 0.003). No SNPs were associated with CY clearance or the ratio of 4HCY/CY AUC after controlling for a false discovery rate.

Conclusion: Age and chemotherapy regimen, but not germline pharmacogenomics, were associated with CY clearance or the ratio of 4HCY/CY AUC. Other methods, such as metabolomics or lipidomics, should be explored.

目的:4-羟基环磷酰胺(4HCY)是环磷酰胺(CY)细胞毒性代谢产物的主要前体,常用于儿童癌症的一线治疗。关于环磷酰胺的疗效、毒性和药代动力学与编码参与 4HCY 药代动力学(特别是其形成和消除)的蛋白质的基因之间的关系,有相互矛盾的数据:我们对首次服用 CY 的各种恶性肿瘤患儿的种系药物遗传学进行了评估。采用线性回归法,我们分析了两种药代动力学结果--儿童清除 CY 的速度(即 CY 清除率)和 4HCY/CY 暴露比值(即血浆浓度-时间曲线下面积(AUC))--与 14 种参与 4HCY 形成或清除的药物代谢转运体或酶中的 372 个单核苷酸多态性(SNP)之间的关联:结果:年龄与 4HCY/CY AUC 的比值相关(P = 0.004);化疗方案与 CY 清除率相关(P = 0.003)。在控制虚假发现率后,没有SNP与CY清除率或4HCY/CY AUC比率相关:结论:年龄和化疗方案与CY清除率或4HCY/CY AUC比值有关,但与种系药物基因组学无关。应探索其他方法,如代谢组学或脂质组学。
{"title":"Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with 4hydroxycyclophosphamide formation in children with Cancer.","authors":"Sandi L Navarro, Navin Pinto, Douglas S Hawkins, Julie R Park, Saam Dilmaghani, Christine Rimorin, Michelle Wurscher, Jeannine S McCune","doi":"10.1007/s00280-024-04703-2","DOIUrl":"10.1007/s00280-024-04703-2","url":null,"abstract":"<p><strong>Purpose: </strong>4-hydroxycyclophosphamide (4HCY) is the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY), which is often used as first-line treatment of children with cancer. There is conflicting data regarding the relationship between CY efficacy, toxicity, and pharmacokinetics with the genes encoding proteins involved in 4HCY pharmacokinetics, specifically its formation and elimination.</p><p><strong>Methods: </strong>We evaluated germline pharmacogenetics in children with various malignancies receiving their first CY dose. Using linear regression, we analyzed the associations between two pharmacokinetic outcomes - how fast a child cleared CY (i.e., CY clearance) and the ratio of the 4HCY/CY exposure, specifically area under the plasma concentration-time curve (AUC), and 372 single nucleotide polymorphisms (SNP) in 14 drug-metabolizing transporters or enzymes involved in 4HCY formation or elimination.</p><p><strong>Results: </strong>Age was associated with the ratio of 4HCY/CY AUC (P = 0.004); Chemotherapy regimen was associated with CY clearance (P = 0.003). No SNPs were associated with CY clearance or the ratio of 4HCY/CY AUC after controlling for a false discovery rate.</p><p><strong>Conclusion: </strong>Age and chemotherapy regimen, but not germline pharmacogenomics, were associated with CY clearance or the ratio of 4HCY/CY AUC. Other methods, such as metabolomics or lipidomics, should be explored.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"627-633"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dexamethasone reduces cisplatin-induced hair cell damage by inducing cisplatin resistance through metallothionein-2. 地塞米松通过金属硫蛋白-2诱导顺铂抗性,从而减轻顺铂诱导的毛细胞损伤。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1007/s00280-024-04706-z
Haruki Ujiie, Naoyuki Nishiya, Ami Yamamoto, Takeru Takada, Megumi Onodera, Ayana Sasaki, Takuya Oikawa

Purpose: Hair cell damage is a common side effect caused by the anticancer drug cisplatin (CDDP), which reduces patient quality of life. One CDDP resistance mechanism that occurs in recurrent cancers is heavy metal detoxification by metallothionein-2 (mt2). Here, we show that in zebrafish larvae, dexamethasone (DEX) reduces CDDP-induced hair cell damage by enhancing mt2 expression.

Methods: Transgenic zebrafish (cldn: gfp; atoh1: rfp) that express green and red fluorescent proteins in neuromasts and hair cells, respectively, were used. The zebrafish were pretreated with DEX at 52 h post-fertilization (hpf) for 8 h, followed by CDDP treatment for 12 h. The lateral line hair cells of CDDP-treated zebrafish at 72 hpf were observed by fluorescence microscopy.

Results: Reporting odds ratio (ROR) analysis using an adverse event database indicated an association between a decrease in CDDP-induced ototoxicity and DEX as an antiemetic treatment for cancer chemotherapy. Pretreatment with DEX protected 72 hpf zebrafish hair cells from CDDP-induced damage. The expression of mt2 mRNA was significantly increased by the combination of 10 µM DEX with CDDP. Gene editing of mt2 reversed the protective effect of DEX against CDDP-induced damage in hair cells.

Conclusion: DEX protects hair cells from CDDP-induced damage through increased mt2 expression, which is a resistance mechanism for platinum-based anticancer drugs.

目的:毛细胞损伤是抗癌药物顺铂(CDDP)引起的常见副作用,会降低患者的生活质量。复发性癌症中出现的一种 CDDP 抵抗机制是金属硫蛋白-2(mt2)对重金属的解毒作用。在这里,我们发现在斑马鱼幼体中,地塞米松(DEX)可通过增强 mt2 的表达来减少 CDDP 诱导的毛细胞损伤:方法:使用在神经细胞和毛细胞中分别表达绿色和红色荧光蛋白的转基因斑马鱼(cldn: gfp; atoh1: rfp)。在受精后52 hpf用DEX预处理斑马鱼8 h,然后用CDDP处理12 hpf,用荧光显微镜观察72 hpf时CDDP处理斑马鱼的侧线毛细胞:结果:利用不良事件数据库进行的报告几率比(ROR)分析表明,CDDP诱发的耳毒性降低与作为癌症化疗止吐药的DEX之间存在关联。预处理DEX可保护72 hpf斑马鱼毛细胞免受CDDP诱导的损伤。10 µM DEX与CDDP联用可显著增加mt2 mRNA的表达。mt2的基因编辑逆转了DEX对CDDP诱导的毛细胞损伤的保护作用:结论:DEX通过增加mt2的表达保护毛细胞免受CDDP诱导的损伤,而mt2是铂类抗癌药物的一种抗药机制。
{"title":"Dexamethasone reduces cisplatin-induced hair cell damage by inducing cisplatin resistance through metallothionein-2.","authors":"Haruki Ujiie, Naoyuki Nishiya, Ami Yamamoto, Takeru Takada, Megumi Onodera, Ayana Sasaki, Takuya Oikawa","doi":"10.1007/s00280-024-04706-z","DOIUrl":"10.1007/s00280-024-04706-z","url":null,"abstract":"<p><strong>Purpose: </strong>Hair cell damage is a common side effect caused by the anticancer drug cisplatin (CDDP), which reduces patient quality of life. One CDDP resistance mechanism that occurs in recurrent cancers is heavy metal detoxification by metallothionein-2 (mt2). Here, we show that in zebrafish larvae, dexamethasone (DEX) reduces CDDP-induced hair cell damage by enhancing mt2 expression.</p><p><strong>Methods: </strong>Transgenic zebrafish (cldn: gfp; atoh1: rfp) that express green and red fluorescent proteins in neuromasts and hair cells, respectively, were used. The zebrafish were pretreated with DEX at 52 h post-fertilization (hpf) for 8 h, followed by CDDP treatment for 12 h. The lateral line hair cells of CDDP-treated zebrafish at 72 hpf were observed by fluorescence microscopy.</p><p><strong>Results: </strong>Reporting odds ratio (ROR) analysis using an adverse event database indicated an association between a decrease in CDDP-induced ototoxicity and DEX as an antiemetic treatment for cancer chemotherapy. Pretreatment with DEX protected 72 hpf zebrafish hair cells from CDDP-induced damage. The expression of mt2 mRNA was significantly increased by the combination of 10 µM DEX with CDDP. Gene editing of mt2 reversed the protective effect of DEX against CDDP-induced damage in hair cells.</p><p><strong>Conclusion: </strong>DEX protects hair cells from CDDP-induced damage through increased mt2 expression, which is a resistance mechanism for platinum-based anticancer drugs.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"561-569"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Low serum concentrations of bevacizumab and nivolumab owing to excessive urinary loss in patients with proteinuria: a case series. 蛋白尿患者因尿液流失过多导致贝伐珠单抗和尼伐单抗血清浓度过低:一个病例系列。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-03-08 DOI: 10.1007/s00280-024-04659-3
Takashi Masuda, Taro Funakoshi, Takahiro Horimatsu, Shinya Yamamoto, Takeshi Matsubara, Sho Masui, Shunsaku Nakagawa, Yasuaki Ikemi, Motoko Yanagita, Manabu Muto, Tomohiro Terada, Atsushi Yonezawa

Purpose: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients.

Methods: Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry.

Results: We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase.

Conclusion: This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.

目的:蛋白尿可导致治疗性抗体药代动力学的个体差异,并可能影响疗效。在此,我们测量了蛋白尿患者血清和尿液中贝伐单抗(BV)和尼伐单抗(NIVO)的浓度,并报告了这些患者的病例系列:本研究共纳入了 32 名癌症患者,他们于 2020 年 11 月至 2021 年 9 月期间在京都大学医院接受了每 3 周一次的贝伐单抗或每 2 周一次的 NIVO 治疗。采用液相色谱-串联质谱法测量了血清和尿液中 BV 和 NIVO 的浓度:根据尿蛋白-肌酐比值(UPCR),我们将 BV 治疗患者和 NIVO 治疗患者分为两组:UPCR为1 g/g或更高(BV,9人;NIVO,3人),UPCR低于1 g/g(BV,14人;NIVO,6人)。与 UPCR 小于 1 g/g 的患者相比,BV 和 NIVO 治疗的 UPCR 为 1 g/g 或以上的患者血清中按剂量调整的治疗性抗体浓度明显较低。在 UPCR 为 1 g/g 或更高的患者中,根据血清浓度和尿肌酐浓度调整的治疗性抗体的尿液浓度呈上升趋势:这项病例系列研究表明,蛋白尿患者通过尿液排泄 BV 和 NIVO 有可能降低这些药物的血清浓度。
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引用次数: 0
The Gustave Roussy Immune score is a powerful biomarker for predicting therapeutic resistance to chemotherapy in gastric cancer patients. 古斯塔夫-鲁西(Gustave Roussy)免疫评分是预测胃癌患者化疗耐药性的有力生物标志物。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-25 DOI: 10.1007/s00280-024-04692-2
Nobuhiro Nakazawa, Makoto Sohda, Mizuki Endo, Nobuhiro Hosoi, Shintaro Uchida, Takayoshi Watanabe, Akihiko Sano, Makoto Sakai, Hiroomi Ogawa, Ken Shirabe, Hiroshi Saeki

Purpose: It is highly important to be able to predict the therapeutic efficacy of chemotherapy on patients with unresectable advanced or recurrent gastric cancer (GC). The Gustave Roussy Immune Score (GRIm-s) is a predictor of therapeutic sensitivity to chemotherapy and immune checkpoint inhibitors (ICIs) in other cancers. The present study aimed to analyze the association of the GRIm-s with the therapeutic sensitivity of first-line chemotherapy in GC patients.

Methods: We included 156 patients receiving primary chemotherapy treatment for unresectable or advanced recurrent GC between January 2012 and December 2021 at our institution. We evaluated the correlation between the GRIm-s and therapeutic sensitivities to chemotherapy. The GRIm-s was assessed before the start of first-line chemotherapy.

Results: Among the 156 patients, 138 (88.5%) and 18 (11.5%) were classified in the low- and high-risk groups, respectively. The GRIm-s high-risk group was significantly older (p = 0.013), had more advanced unresectable cancer (p = 0.0098), and was significantly less likely to progress to second-line chemotherapy (p = 0.014). The overall survival rate (OS) (p = 0.039) and the progression free survival rate (PFS) (p = 0.017) were significantly worse in the GRIm-s high-risk group. The high GRIm-s was an independent prognostic factor for poor survival in multivariate analysis (p = 0.0094).

Conclusions: Focusing on the GRIm-s before first-line chemotherapy initiation for unresectable advanced or postoperative recurrent GC was useful in predicting the therapeutic resistance to chemotherapy, transition to second-line chemotherapy, and poor prognosis.

目的:预测化疗对无法切除的晚期或复发性胃癌(GC)患者的疗效非常重要。古斯塔夫-鲁西免疫评分(GRIm-s)是预测其他癌症患者对化疗和免疫检查点抑制剂(ICIs)治疗敏感性的指标。本研究旨在分析GRIm-s与GC患者一线化疗治疗敏感性的关系:我们纳入了 2012 年 1 月至 2021 年 12 月期间在我院接受一线化疗治疗的 156 例不可切除或晚期复发 GC 患者。我们评估了GRIm-s与化疗敏感性之间的相关性。GRIm-s在一线化疗开始前进行评估:156例患者中,138例(88.5%)和18例(11.5%)分别被归入低危和高危组。GRIm-s高风险组患者年龄明显偏大(p = 0.013),不可切除癌症的晚期程度更高(p = 0.0098),接受二线化疗的几率明显更低(p = 0.014)。GRIm-s高风险组的总生存率(OS)(p = 0.039)和无进展生存率(PFS)(p = 0.017)明显更差。在多变量分析中,高GRIm-s是生存率低的独立预后因素(p = 0.0094):结论:对于不可切除的晚期或术后复发 GC,在开始一线化疗前关注 GRIm-s,有助于预测化疗耐药、向二线化疗过渡以及不良预后。
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引用次数: 0
Successful use of Palbociclib combined with Venetoclax and Azacitidine in an adult with refractory/relapsed therapy-related acute myeloid leukemia. 成功将 Palbociclib 与 Venetoclax 和阿扎胞苷联合用于一名患有难治性/复发性治疗相关急性髓性白血病的成人患者。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-03-02 DOI: 10.1007/s00280-024-04642-y
Wenqiang Qu, Jialing Lu, Yujie Ji, Zhewei He, Mengjia Hou, Dongyang Li, Yan Yang, Dan Liu, Suning Chen

Background: Therapy-related acute myeloid leukemia (t-AML) is considered high risk as it related to prior exposure to cytotoxic chemotherapy agents for solid tumors or hematologic malignancies. Compared with de novo AML, t-AML is associated with lower remission rates, inferior overall survival (OS) and higher relapse rates. Many efforts have been devoted to improving the overall but with limited success, and novel strategy is thus highly needed.

Case description: We reported one patient with refractory/relapsed t-AML was successfully treated with Palbociclib combined with Venetoclax and Azacytidine (AZA). In this case, a 47-year-old patient with t-AML recurred during Venetoclax in combination with AZA therapy. However, the patient achieved morphological, immunophenotypic and molecular complete remission again after Palbociclib combined with Venetoclax and AZA.

Conclusions: Although only one successful case is presented here, three-drug combination regimens should be considered as another treatment option for t-AML in the future.

背景:与治疗相关的急性髓性白血病(t-AML)被认为是一种高风险疾病,因为它与之前接触过治疗实体瘤或血液系统恶性肿瘤的细胞毒性化疗药物有关。与新发急性髓细胞白血病相比,t-AML 的缓解率较低,总生存期(OS)较差,复发率较高。人们一直在努力提高总生存率,但收效甚微,因此亟需新的治疗策略:我们报道了一位难治/复发的 t-AML 患者成功接受了 Palbociclib 联合 Venetoclax 和氮杂胞苷(AZA)的治疗。在该病例中,一名47岁的t-AML患者在Venetoclax联合AZA治疗期间复发。然而,在Palbociclib联合Venetoclax和AZA治疗后,患者再次获得了形态学、免疫表型和分子学上的完全缓解:虽然本文仅介绍了一个成功病例,但三药联合治疗方案应被视为未来治疗t-AML的另一种选择。
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引用次数: 0
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Cancer Chemotherapy and Pharmacology
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