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Pharmacokinetics, mass balance, and metabolism of [14C]envonalkib (TQ-B3139), a novel ALK tyrosine kinase inhibitor, in healthy Chinese subjects. 新型ALK酪氨酸激酶抑制剂[14C]envonalkib(TQ-B3139)在中国健康受试者中的药代动力学、质量平衡和代谢。
IF 2.7 4区 医学
Cancer Chemotherapy and Pharmacology Pub Date : 2024-11-01 Epub Date: 2024-03-20 DOI: 10.1007/s00280-024-04647-7
Sheng Ma, Xin Wang, Shu Yan, Liyan Miao, Xiaojing Wan, Dawei Ding, Ding Yu, Xingxing Diao, Xunqiang Wang, Hua Zhang
{"title":"Pharmacokinetics, mass balance, and metabolism of [<sup>14</sup>C]envonalkib (TQ-B3139), a novel ALK tyrosine kinase inhibitor, in healthy Chinese subjects.","authors":"Sheng Ma, Xin Wang, Shu Yan, Liyan Miao, Xiaojing Wan, Dawei Ding, Ding Yu, Xingxing Diao, Xunqiang Wang, Hua Zhang","doi":"10.1007/s00280-024-04647-7","DOIUrl":"10.1007/s00280-024-04647-7","url":null,"abstract":"<p><strong>Purpose: </strong>Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of <sup>14</sup>C-radiolabeled envonalkib in healthy Chinese male subjects.</p><p><strong>Methods: </strong>A single oral dose of 600 mg (150 µCi) [<sup>14</sup>C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification.</p><p><strong>Results: </strong>After dosing, the median T<sub>max</sub> of radioactivity was 4 h and the mean t<sub>1/2</sub> was 65.2 h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504 h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study.</p><p><strong>Conclusion: </strong>Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"647-657"},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140173845","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
Selinexor targeting XPO1 promotes PEG3 nuclear accumulation and suppresses cholangiocarcinoma progression. 以 XPO1 为靶点的 Selinexor 可促进 PEG3 的核积累并抑制胆管癌的进展。
IF 2.7 4区 医学
Cancer Chemotherapy and Pharmacology Pub Date : 2024-11-01 Epub Date: 2024-08-05 DOI: 10.1007/s00280-024-04704-1
Deng Xiang, Min Wang, Huajun Wu, Xi Chen, Tianxiang Chen, Dongshan Yu, Lei Xiong, Han Xu, Ming Luo, Shouhua Zhang, Linquan Wu, Jinlong Yan
{"title":"Selinexor targeting XPO1 promotes PEG3 nuclear accumulation and suppresses cholangiocarcinoma progression.","authors":"Deng Xiang, Min Wang, Huajun Wu, Xi Chen, Tianxiang Chen, Dongshan Yu, Lei Xiong, Han Xu, Ming Luo, Shouhua Zhang, Linquan Wu, Jinlong Yan","doi":"10.1007/s00280-024-04704-1","DOIUrl":"10.1007/s00280-024-04704-1","url":null,"abstract":"<p><strong>Background: </strong>The role of selinexor, a targeted inhibitor of exportin 1 (XPO1), in the treatment of cholangiocarcinoma is not yet fully understood. This study conducted comprehensive in vitro and in vivo investigations to elucidate the effects of selinexor on cholangiocarcinoma, with a focus on its mechanistic relationship with the cellular localization of Paternally Expressed Gene 3 (PEG3).</p><p><strong>Methods: </strong>A patient-derived xenograft (PDX) model was established using samples from a cholangiocarcinoma patient in immunodeficient mice to assess the in vivo effects of selinexor. Additionally, cholangiocarcinoma cell lines HuCC-T1 and BRE were cultured to evaluate selinexor's impact on cell proliferation, invasion, migration, cell cycle, and apoptosis. HuCC-T1 cells were also implanted in immunodeficient mice for further investigation. Immunofluorescence and Western blotting were employed to observe the expression and localization of the PEG3 protein.</p><p><strong>Results: </strong>The results demonstrated that selinexor significantly inhibited tumor growth in the cholangiocarcinoma PDX model and promoted the accumulation of PEG3 protein within the nuclei of tumor cells. In vitro experiments showed that selinexor effectively suppressed cholangiocarcinoma cell proliferation, invasion, and migration, while also impeding the cell cycle and inducing apoptosis. Notably, selinexor markedly facilitated the nuclear accumulation of PEG3 protein in cholangiocarcinoma cells. However, when PEG3 expression was knocked down, the effects of selinexor on cholangiocarcinoma were significantly reversed.</p><p><strong>Conclusion: </strong>These findings suggest that selinexor inhibits the progression of cholangiocarcinoma by targeting XPO1 and promoting the nuclear accumulation of PEG3 protein, thereby hindering the cell cycle and inducing apoptosis.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"669-683"},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892958","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
Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer. 晚期癌症患者使用低剂量 nivolumab(相对于常规剂量)的药代动力学和临床疗效。
IF 2.7 4区 医学
Cancer Chemotherapy and Pharmacology Pub Date : 2024-11-01 Epub Date: 2024-07-26 DOI: 10.1007/s00280-024-04697-x
Khushboo A Gandhi, Aditi Shirsat, Sharat Kumar Hj, Ashish Chavan, Parnika Dicholkar, Saniya Shah, Nandini Menon, Vanita Noronha, Amit Joshi, Kumar Prabhash, Vijay Patil, Vikram Gota
{"title":"Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer.","authors":"Khushboo A Gandhi, Aditi Shirsat, Sharat Kumar Hj, Ashish Chavan, Parnika Dicholkar, Saniya Shah, Nandini Menon, Vanita Noronha, Amit Joshi, Kumar Prabhash, Vijay Patil, Vikram Gota","doi":"10.1007/s00280-024-04697-x","DOIUrl":"10.1007/s00280-024-04697-x","url":null,"abstract":"<p><strong>Purpose: </strong>Nivolumab is approved at various doses, including 3 mg/kg, 240 mg and 480 mg flat doses at various dosing intervals. The concept of low-dose immunotherapy is gaining traction in recent years. However, there is a need to better understand the pharmacokinetics and clinical outcomes at lower doses.</p><p><strong>Methods: </strong>Patients were either administered 40 mg flat dose or 3 mg/kg Q2W/Q3W, depending on affordability as per prevailing hospital practice. All patients were hospitalized on day 1 and pharmacokinetic samples were collected at 0, 0.5, 1.0, 6.0, 24.0, 72.0 h and day 14 following administration of the first dose of nivolumab. Plasma nivolumab levels were measured by ELISA. Patients were followed up for response and toxicity.</p><p><strong>Results: </strong>Twenty five patients were included in the study. Fourteen received nivolumab at conventional dose (3 mg/kg), while 11 patients received low-dose (40 mg flat). The geometric means of dose normalized C<sub>max</sub> and AUC<sub>0-t</sub> were comparable between those who received conventional dose and low-dose of nivolumab (0.28 versus 0.23 µg/mL/mg and 0.0014 versus 0.0011 d/mL respectively). Nineteen patients were evaluable for response. ORR among patients who received conventional dose was 5/11 (45.5%) whereas it was 4/9 (44.4%) in the low-dose cohort. All 14 (100%) patients in conventional dosing group and 7/11 patients (63.64%) in low-dose group had treatment emergent adverse events. Grade ≥ 3 toxicities were observed in 4/14 patients in conventional dose group and none in low-dose group.</p><p><strong>Conclusion: </strong>Low-dose nivolumab leads to lower exposure in patients as compared with conventional dose, but low-dose was better tolerated, while response rates were comparable to conventional dose.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"659-668"},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765554","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
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
Cancer Chemotherapy and Pharmacology 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
{"title":"Pharmacokinetics of trastuzumab and its efficacy and safety in HER2-positive cancer patients.","authors":"Xinyu Luo, Nan Wang, Yue Xing, Xinyue Gao, Yang Yu, Tong Liu, Shuai Jiang, Mei Dong","doi":"10.1007/s00280-024-04707-y","DOIUrl":"10.1007/s00280-024-04707-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"721-732"},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035276","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
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
Cancer Chemotherapy and Pharmacology 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
{"title":"An interactive dose optimizer based on population pharmacokinetic study to guide dosing of methotrexate in Chinese patients with osteosarcoma.","authors":"Yanjie Zhang, Xiemin Qi, Xiaohui Huang, Xiaozhou Liu, Yanyu Liu, Jianzhong Rui, Qiong Yin, Sujia Wu, Guohua Zhou","doi":"10.1007/s00280-024-04708-x","DOIUrl":"10.1007/s00280-024-04708-x","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Method: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>The dose optimizer tool could be used to estimate individual PK parameters, and optimize personalized MTX therapy in particular patients.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"733-745"},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046414","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
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
Cancer Chemotherapy and Pharmacology 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
{"title":"Population pharmacokinetic and exposure-toxicity analyses of nab-paclitaxel after pegylated recombinant human granulocyte colony-stimulating factor administration in patients with metastatic breast cancer.","authors":"Dihong Yang, Gaoqi Xu, Haiying Ding, Like Zhong, Junfeng Zhu, Xiufang Mi, Wenxiu Xin, Tianyan Zhou, Jiaqi Wang, Luo Fang","doi":"10.1007/s00280-024-04702-3","DOIUrl":"10.1007/s00280-024-04702-3","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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/m<sup>2</sup> 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.</p><p><strong>Results: </strong>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 (r<sup>2</sup> = 0.23, P = 0.00062). Specifically, a duration of > 8.6 h was a predictor of a decreased neutrophil count.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"523-534"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854939","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
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
Cancer Chemotherapy and Pharmacology 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
{"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
Cancer Chemotherapy and Pharmacology 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
{"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
Cancer Chemotherapy and Pharmacology 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
{"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
Cancer Chemotherapy and Pharmacology 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
{"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
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