Pub Date : 2024-12-01Epub Date: 2024-10-04DOI: 10.1007/s00280-024-04717-w
N de Rouw, R Beunders, O Hartmann, J Schulte, R J Boosman, H J Derijks, D M Burger, M M van den Heuvel, L B Hilbrands, P Pickkers, R Ter Heine
Introduction: For drugs with a narrow therapeutic window, there is a delicate balance between efficacy and toxicity, thus it is pivotal to administer the right dose from the first administration onwards. Exposure of pemetrexed, a cytotoxic drug used in lung cancer treatment, is dictated by kidney function. To facilitate optimized dosing of pemetrexed, accurate prediction of drug clearance is pivotal. Therefore, the aim of this study was to investigate the performance of the kidney function biomarkers serum creatinine, cystatin C and pro-enkephalin in terms of predicting the elimination of pemetrexed.
Methods: We performed a population pharmacokinetic analysis using a dataset from two clinical trials containing pharmacokinetic data of pemetrexed and measurements of all three biomarkers. A three-compartment model without covariates was fitted to the data and the obtained individual empirical Bayes estimates for pemetrexed clearance were considered the "true" values (Cltrue). Subsequently, the following algorithms were tested as covariates for pemetrexed clearance: the Chronic Kidney Disease Epidemiology Collaboration equation using creatinine (CKD-EPICR), cystatin C (CKD-EPICYS), a combination of both (CKD-EPICR-CYS), pro-enkephalin as an absolute value or in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C.
Results: The dataset consisted of 66 subjects with paired observations for all three kidney function biomarkers. Inclusion of CKD-EPICR-CYS as a covariate on pemetrexed clearance resulted in the best model fit, with the largest decrease in objective function (p < 0.00001) and explaining 35% of the total inter-individual variability in clearance. The predictive performance of the model to containing CKD-EPICR-CYS to predict pemetrexed clearance was good with a normalized root mean squared error and mean prediction error of 19.9% and 1.2%, respectively.
Conclusions: In conclusion, this study showed that the combined CKD-EPICR-CYS performs best in terms predicting pharmacokinetics of pemetrexed. Despite the hypothesized disadvantages, creatinine remains to be a suitable and readily available marker to predict pemetrexed clearance in clinical practice.
简介对于治疗窗口较窄的药物来说,疗效和毒性之间存在着微妙的平衡,因此,从首次给药开始就使用正确的剂量至关重要。培美曲塞是一种用于肺癌治疗的细胞毒性药物,其暴露量受肾功能的影响。为了优化培美曲塞的剂量,准确预测药物清除率至关重要。因此,本研究旨在探讨肾功能生物标志物血清肌酐、胱抑素 C 和原烯脑啡肽在预测培美曲塞清除率方面的性能:我们使用两个临床试验的数据集进行了群体药代动力学分析,其中包含培美曲塞的药代动力学数据和所有三种生物标志物的测量值。对数据拟合了不含协变量的三室模型,并将获得的培美曲塞清除率个体经验贝叶斯估计值视为 "真实 "值(Ctrue)。随后,测试了以下作为培美曲塞清除率协变量的算法:使用肌酐的慢性肾脏病流行病学协作方程(CKD-EPICR)、胱抑素 C(CKD-EPICYS)、两者的组合(CKD-EPICR-CYS)、作为绝对值的原脑啡肽或与年龄和血清肌酐的组合算法,以及原脑啡肽与胱抑素 C 的组合:数据集由 66 名受试者组成,对所有三种肾功能生物标志物进行了配对观察。将 CKD-EPICR-CYS 作为培美曲塞清除率的协变量可使模型拟合效果最佳,目标函数(p CR-CYS 预测培美曲塞清除率的归一化均方根误差和平均预测误差分别为 19.9% 和 1.2%)下降幅度最大:总之,本研究表明,CKD-EPICR-CYS 组合在预测培美曲塞的药代动力学方面表现最佳。尽管存在假设的缺点,但在临床实践中,肌酐仍是预测培美曲塞清除率的一个合适且易于使用的指标。
{"title":"A comparison of the renal function biomarkers serum creatinine, pro-enkephalin and cystatin C to predict clearance of pemetrexed.","authors":"N de Rouw, R Beunders, O Hartmann, J Schulte, R J Boosman, H J Derijks, D M Burger, M M van den Heuvel, L B Hilbrands, P Pickkers, R Ter Heine","doi":"10.1007/s00280-024-04717-w","DOIUrl":"10.1007/s00280-024-04717-w","url":null,"abstract":"<p><strong>Introduction: </strong>For drugs with a narrow therapeutic window, there is a delicate balance between efficacy and toxicity, thus it is pivotal to administer the right dose from the first administration onwards. Exposure of pemetrexed, a cytotoxic drug used in lung cancer treatment, is dictated by kidney function. To facilitate optimized dosing of pemetrexed, accurate prediction of drug clearance is pivotal. Therefore, the aim of this study was to investigate the performance of the kidney function biomarkers serum creatinine, cystatin C and pro-enkephalin in terms of predicting the elimination of pemetrexed.</p><p><strong>Methods: </strong>We performed a population pharmacokinetic analysis using a dataset from two clinical trials containing pharmacokinetic data of pemetrexed and measurements of all three biomarkers. A three-compartment model without covariates was fitted to the data and the obtained individual empirical Bayes estimates for pemetrexed clearance were considered the \"true\" values (Cl<sub>true</sub>). Subsequently, the following algorithms were tested as covariates for pemetrexed clearance: the Chronic Kidney Disease Epidemiology Collaboration equation using creatinine (CKD-EPI<sub>CR</sub>), cystatin C (CKD-EPI<sub>CYS</sub>), a combination of both (CKD-EPI<sub>CR-CYS</sub>), pro-enkephalin as an absolute value or in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C.</p><p><strong>Results: </strong>The dataset consisted of 66 subjects with paired observations for all three kidney function biomarkers. Inclusion of CKD-EPI<sub>CR-CYS</sub> as a covariate on pemetrexed clearance resulted in the best model fit, with the largest decrease in objective function (p < 0.00001) and explaining 35% of the total inter-individual variability in clearance. The predictive performance of the model to containing CKD-EPI<sub>CR-CYS</sub> to predict pemetrexed clearance was good with a normalized root mean squared error and mean prediction error of 19.9% and 1.2%, respectively.</p><p><strong>Conclusions: </strong>In conclusion, this study showed that the combined CKD-EPI<sub>CR-CYS</sub> performs best in terms predicting pharmacokinetics of pemetrexed. Despite the hypothesized disadvantages, creatinine remains to be a suitable and readily available marker to predict pemetrexed clearance in clinical practice.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"799-806"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371051","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}
Pub Date : 2024-12-01Epub Date: 2024-10-19DOI: 10.1007/s00280-024-04719-8
Hazal Kayikci, C Tuccar, E Damadoglu, G Karakaya, A F Kalyoncu
Introduction: Regorafenib is an oral protein kinase inhinitor approved fot the treatment of metastatic colorecral cancer. We present a first successful case of desensitization in regorafenib-related fix-drug eruption in the literature.
Case report: A 44-year-old female patient was diagnosed with metastatic colorectal adenocarcinoma. The patient received regorafenib treatment for malignancy recurrence. The patient was admitted to adult allergy clinic with developing recurrent fix drug eruption in the second cycle, on the 10th day of regorafenib treatment. The patient was given the third cycle of regorafenib treatment with a 6-day desensitization protocol, the first day of which consisted of 6 steps and and the third cycle was successfully completed.
Management and outcome: Regorafenib-mediated delayed hypersensitivity reactions occur less frequently and and regorafenib hypersensitivity reactions are difficult to manage and experience is limited. This is the first successful desensitization protocol developed by us for regorafenib-related fix drug eruption and more cases are needed to be reported to confirm the desensitization protocol.
Discussion: There is only one successful regorafenib desensitization protocol for severe delayed hypersensivity reaction in the literature, but there is no protocol developed for mild type delayed hypersensivity reaction. The management of fix-drug eruption primarily involves discontinuation and avoidance of the offending drug but our patient had a mild delayed-type reaction and there was no alternative to regarofenib treatment. We developed the rapid 6-step desensitization protocol (Day 1). According to this protocol, the patient was able to continue regorafenib treatment successfully.
{"title":"Successful desensitization in a patient with metastatic colorectal cancer presenting with regorafenib-mediated fix drug eruption.","authors":"Hazal Kayikci, C Tuccar, E Damadoglu, G Karakaya, A F Kalyoncu","doi":"10.1007/s00280-024-04719-8","DOIUrl":"10.1007/s00280-024-04719-8","url":null,"abstract":"<p><strong>Introduction: </strong>Regorafenib is an oral protein kinase inhinitor approved fot the treatment of metastatic colorecral cancer. We present a first successful case of desensitization in regorafenib-related fix-drug eruption in the literature.</p><p><strong>Case report: </strong>A 44-year-old female patient was diagnosed with metastatic colorectal adenocarcinoma. The patient received regorafenib treatment for malignancy recurrence. The patient was admitted to adult allergy clinic with developing recurrent fix drug eruption in the second cycle, on the 10th day of regorafenib treatment. The patient was given the third cycle of regorafenib treatment with a 6-day desensitization protocol, the first day of which consisted of 6 steps and and the third cycle was successfully completed.</p><p><strong>Management and outcome: </strong>Regorafenib-mediated delayed hypersensitivity reactions occur less frequently and and regorafenib hypersensitivity reactions are difficult to manage and experience is limited. This is the first successful desensitization protocol developed by us for regorafenib-related fix drug eruption and more cases are needed to be reported to confirm the desensitization protocol.</p><p><strong>Discussion: </strong>There is only one successful regorafenib desensitization protocol for severe delayed hypersensivity reaction in the literature, but there is no protocol developed for mild type delayed hypersensivity reaction. The management of fix-drug eruption primarily involves discontinuation and avoidance of the offending drug but our patient had a mild delayed-type reaction and there was no alternative to regarofenib treatment. We developed the rapid 6-step desensitization protocol (Day 1). According to this protocol, the patient was able to continue regorafenib treatment successfully.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"815-818"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458679","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}
Pub Date : 2024-12-01Epub Date: 2024-09-23DOI: 10.1007/s00280-024-04714-z
Apostolia Maria Tsimberidou, Axel Grothey, Darren Sigal, Heinz-Josef Lenz, Howard S Hochster, Yee Chao, Li-Yuan Bai, Chia-Jui L Yen, Dong Xu, M Wayne Saville
Purpose: OBI-888 is a humanized, monoclonal IgG1 antibody specific to the tumor-associated carbohydrate antigen Globo H. We conducted a phase I-II study of OBI-888 in patients with advanced cancer.
Methods: Patients were treated with OBI-888 5, 10, or 20 mg/kg IV weekly in Part A ("3 + 3" design) and 20 mg/kg IV weekly in Part B (Simon's 2-stage design) (1 cycle = 28 days).
Results: Overall, 54 patients were treated (Part A, n = 14; Part B, n = 40). OBI-888 was safe and well tolerated across the doses studied, with a low incidence of OBI-888-related treatment emergent adverse events. The maximum tolerated dose of OBI-888 was not reached. No dose-limiting toxicities were noted up to the 20 mg/kg dose level (recommended phase 2 dose). Stable disease (SD) was noted in 28.6% and 20% of Parts A and B, respectively, including three patients with SD for 6+, 7+, and 9 months. Antibody-dependent cellular cytotoxicity (ADCC) was induced after each OBI-888 treatment (average increase, 3.8-fold and 4.7-fold in Parts A and B, respectively), suggesting that ADCC induction is a potential mechanism of action of OBI-888.
Conclusions: OBI-888 was well tolerated. Prolonged SD was noted in three patients. ADCC was induced after each OBI-888 treatment.
{"title":"Phase I-II study of OBI-888, a humanized monoclonal IgG1 antibody against the tumor-associated carbohydrate antigen Globo H, in patients with advanced solid tumors.","authors":"Apostolia Maria Tsimberidou, Axel Grothey, Darren Sigal, Heinz-Josef Lenz, Howard S Hochster, Yee Chao, Li-Yuan Bai, Chia-Jui L Yen, Dong Xu, M Wayne Saville","doi":"10.1007/s00280-024-04714-z","DOIUrl":"10.1007/s00280-024-04714-z","url":null,"abstract":"<p><strong>Purpose: </strong>OBI-888 is a humanized, monoclonal IgG1 antibody specific to the tumor-associated carbohydrate antigen Globo H. We conducted a phase I-II study of OBI-888 in patients with advanced cancer.</p><p><strong>Methods: </strong>Patients were treated with OBI-888 5, 10, or 20 mg/kg IV weekly in Part A (\"3 + 3\" design) and 20 mg/kg IV weekly in Part B (Simon's 2-stage design) (1 cycle = 28 days).</p><p><strong>Results: </strong>Overall, 54 patients were treated (Part A, n = 14; Part B, n = 40). OBI-888 was safe and well tolerated across the doses studied, with a low incidence of OBI-888-related treatment emergent adverse events. The maximum tolerated dose of OBI-888 was not reached. No dose-limiting toxicities were noted up to the 20 mg/kg dose level (recommended phase 2 dose). Stable disease (SD) was noted in 28.6% and 20% of Parts A and B, respectively, including three patients with SD for 6+, 7+, and 9 months. Antibody-dependent cellular cytotoxicity (ADCC) was induced after each OBI-888 treatment (average increase, 3.8-fold and 4.7-fold in Parts A and B, respectively), suggesting that ADCC induction is a potential mechanism of action of OBI-888.</p><p><strong>Conclusions: </strong>OBI-888 was well tolerated. Prolonged SD was noted in three patients. ADCC was induced after each OBI-888 treatment.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"787-798"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280630","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}
Pub Date : 2024-12-01Epub Date: 2024-10-18DOI: 10.1007/s00280-024-04711-2
Zeynep Eroglu, Timothy Synold, Behnam Badie, An Liu, Arnab Chowdhury, Julie Kilpatrick, Suzette Blanchard, Jana Portnow
Purpose: Eribulin is an inhibitor of microtubule dynamics. It is not as highly protein bound as the taxanes and is less vulnerable to extrusion by P-glycoprotein in the blood-brain barrier (BBB). These features predict that eribulin could play an active role in managing brain tumors. Indeed, the small amount of published clinical data indicates eribulin may have some efficacy against breast cancer brain metastases. To better understand the potential of eribulin for treating brain tumors, we performed an intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in cancer patients undergoing tumor resection.
Methods: After tumor removal, two microdialysis catheters were inserted into peritumoral brain tissue. Approximately 24 h after surgery, a single dose of eribulin 1.4 mg/m2 was administered intravenously. Dialysate samples were collected continuously for 72 h, with plasma samples collected in parallel. Eribulin concentrations were analyzed by tandem mass spectrometry.
Results: Dialysate samples from 12 intracerebral microdialysis catheters placed in 7 study participants were included in the analysis. A statistically significant difference was observed between eribulin concentrations in brain tissue where BBB was disrupted versus intact, with a difference in mean maximum concentrations on log2 scale of 3.37 (std err = 0.59, p-value = 0.005). Nonetheless, overall brain to plasma ratios of eribulin only ranged from 0.13 to 1.99%.
Conclusion: Although we could detect higher concentrations of eribulin in brain tissue where BBB was disrupted, intracerebral eribulin levels were not sufficient to predict eribulin would have consistent clinically meaningful activity against tumors in the brain.
{"title":"An intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in patients with metastatic or primary brain tumors.","authors":"Zeynep Eroglu, Timothy Synold, Behnam Badie, An Liu, Arnab Chowdhury, Julie Kilpatrick, Suzette Blanchard, Jana Portnow","doi":"10.1007/s00280-024-04711-2","DOIUrl":"10.1007/s00280-024-04711-2","url":null,"abstract":"<p><strong>Purpose: </strong>Eribulin is an inhibitor of microtubule dynamics. It is not as highly protein bound as the taxanes and is less vulnerable to extrusion by P-glycoprotein in the blood-brain barrier (BBB). These features predict that eribulin could play an active role in managing brain tumors. Indeed, the small amount of published clinical data indicates eribulin may have some efficacy against breast cancer brain metastases. To better understand the potential of eribulin for treating brain tumors, we performed an intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in cancer patients undergoing tumor resection.</p><p><strong>Methods: </strong>After tumor removal, two microdialysis catheters were inserted into peritumoral brain tissue. Approximately 24 h after surgery, a single dose of eribulin 1.4 mg/m<sup>2</sup> was administered intravenously. Dialysate samples were collected continuously for 72 h, with plasma samples collected in parallel. Eribulin concentrations were analyzed by tandem mass spectrometry.</p><p><strong>Results: </strong>Dialysate samples from 12 intracerebral microdialysis catheters placed in 7 study participants were included in the analysis. A statistically significant difference was observed between eribulin concentrations in brain tissue where BBB was disrupted versus intact, with a difference in mean maximum concentrations on log<sub>2</sub> scale of 3.37 (std err = 0.59, p-value = 0.005). Nonetheless, overall brain to plasma ratios of eribulin only ranged from 0.13 to 1.99%.</p><p><strong>Conclusion: </strong>Although we could detect higher concentrations of eribulin in brain tissue where BBB was disrupted, intracerebral eribulin levels were not sufficient to predict eribulin would have consistent clinically meaningful activity against tumors in the brain.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT02338037 (January 9, 2015).</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"807-813"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458677","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}
Pub Date : 2024-12-01Epub Date: 2024-09-21DOI: 10.1007/s00280-024-04713-0
Sophie Rex Christensen, Christina Friis Jensen, Jesper Heldrup, Zachary Taylor, Laura B Ramsey, Steen Rosthøj
Purpose: High-dose methotrexate (HDMTX) therapy is an important component in treatment regimens for acute lymphoblastic leukemia (ALL). Courses are associated with a risk of renal injury, delayed elimination, and increased systemic toxicity. Recently hypoalbuminemia has been recognized as yet another risk factor.
Methods: To examine the impact of serum albumin we reviewed 325 HDMTX 5 g/m2 courses in a cohort of 51 children treated on the NOPHO ALL 2008 protocol, dividing the courses into four groups with different levels of baseline albumin (A < 25 g/L, B 25-29 g/L, C 30-34 g/L and D ≥ 35 g/L).
Results: Hypoalbuminemia was present in 51% of the courses, mostly in the early phases of chemotherapy while asparaginase therapy is ongoing, and especially if given less than 2 weeks after a dose (78%). Hypoalbuminemia had a significant impact on the end-of-infusion serum MTX, depending on the degree of hypoalbuminemia: MTX > 150 µM was seen in 37%, 32%, 20% and 8% in groups A to D. Serum albumin < 30 g/L was significantly associated with low MTX clearance < 10 L/h/1.73m2 (78% vs. 36%) and high AUC ≥ 1000 µM*h (44% vs. 31%). The frequency of rising creatinine or prolonged elimination was not increased, but the risk of stomatitis was significantly higher (42% vs. 19%).
Conclusion: Low serum albumin is caused by concurrent asparaginase therapy and has a clinically significant impact on MTX disposition. Guidelines for administering HDMTX may need adjustment if serum albumin < 30 g/L, and, if possible, HDMTX courses should not be scheduled soon after asparaginase doses.
{"title":"Hypoalbuminemia in children with acute lymphoblastic leukemia: relation to asparaginase therapy and impact on high dose methotrexate elimination.","authors":"Sophie Rex Christensen, Christina Friis Jensen, Jesper Heldrup, Zachary Taylor, Laura B Ramsey, Steen Rosthøj","doi":"10.1007/s00280-024-04713-0","DOIUrl":"10.1007/s00280-024-04713-0","url":null,"abstract":"<p><strong>Purpose: </strong>High-dose methotrexate (HDMTX) therapy is an important component in treatment regimens for acute lymphoblastic leukemia (ALL). Courses are associated with a risk of renal injury, delayed elimination, and increased systemic toxicity. Recently hypoalbuminemia has been recognized as yet another risk factor.</p><p><strong>Methods: </strong>To examine the impact of serum albumin we reviewed 325 HDMTX 5 g/m2 courses in a cohort of 51 children treated on the NOPHO ALL 2008 protocol, dividing the courses into four groups with different levels of baseline albumin (A < 25 g/L, B 25-29 g/L, C 30-34 g/L and D ≥ 35 g/L).</p><p><strong>Results: </strong>Hypoalbuminemia was present in 51% of the courses, mostly in the early phases of chemotherapy while asparaginase therapy is ongoing, and especially if given less than 2 weeks after a dose (78%). Hypoalbuminemia had a significant impact on the end-of-infusion serum MTX, depending on the degree of hypoalbuminemia: MTX > 150 µM was seen in 37%, 32%, 20% and 8% in groups A to D. Serum albumin < 30 g/L was significantly associated with low MTX clearance < 10 L/h/1.73m2 (78% vs. 36%) and high AUC ≥ 1000 µM*h (44% vs. 31%). The frequency of rising creatinine or prolonged elimination was not increased, but the risk of stomatitis was significantly higher (42% vs. 19%).</p><p><strong>Conclusion: </strong>Low serum albumin is caused by concurrent asparaginase therapy and has a clinically significant impact on MTX disposition. Guidelines for administering HDMTX may need adjustment if serum albumin < 30 g/L, and, if possible, HDMTX courses should not be scheduled soon after asparaginase doses.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"775-785"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280629","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}
Background: Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer and is frequently resistant to therapy, ultimately resulting in treatment failure. Clinical trials have demonstrated the potential of sensitizing radiation therapy (RT)-resistant TNBC through the combination of chemotherapy and RT. This study sought to explore the potential of CD151 as a therapy response marker in the co-treatment strategy involving ionizing radiation (IR) and the repurposed antiviral drug 2-Thio-6-azauridine (TAU) for sensitizing RT-resistant TNBC (TNBC/RR).
Methods: The investigation encompassed a variety of assessments, including viability using MTT and LDH assays, cell proliferation through BrdU incorporation and clonogenic assays, cell cycle analysis via flow cytometry, cell migration using wound scratch and Boyden chamber invasion assays, DNA damage assessment through γH2AX analysis, apoptosis evaluation through acridine-orange and ethidium bromide double staining assays, as well as caspase 3 activity measurement using a colorimetric assay. CD151 expression was examined through ELISA, flow cytometry and RT-qPCR.
Results: The results showed a significant reduction in TNBC/RR cell viability following co-treatment. Moreover, the co-treatment reduced cell migration, induced apoptosis, downregulated CD151 expression, and increased caspase 3 activity in TNBC/RR cells. Additionally, CD151 was predicted to serve as a therapy response marker for co-treatment with TAU and IR.
Conclusion: These findings suggest the potential of combination treatment with IR and TAU as a promising strategy to overcome RT resistance in TNBC. Furthermore, CD151 emerges as a valuable therapy response marker for chemoradiotherapy.
{"title":"Combination of ionizing radiation and 2-thio-6-azauridine induces cell death in radioresistant triple negative breast cancer cells by downregulating CD151 expression.","authors":"Rakshmitha Marni, Manas Malla, Anindita Chakraborty, Murali Krishna Voonna, Partha Sarathi Bhattacharyya, Deepak Kgk, Rama Rao Malla","doi":"10.1007/s00280-024-04709-w","DOIUrl":"10.1007/s00280-024-04709-w","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer and is frequently resistant to therapy, ultimately resulting in treatment failure. Clinical trials have demonstrated the potential of sensitizing radiation therapy (RT)-resistant TNBC through the combination of chemotherapy and RT. This study sought to explore the potential of CD151 as a therapy response marker in the co-treatment strategy involving ionizing radiation (IR) and the repurposed antiviral drug 2-Thio-6-azauridine (TAU) for sensitizing RT-resistant TNBC (TNBC/RR).</p><p><strong>Methods: </strong>The investigation encompassed a variety of assessments, including viability using MTT and LDH assays, cell proliferation through BrdU incorporation and clonogenic assays, cell cycle analysis via flow cytometry, cell migration using wound scratch and Boyden chamber invasion assays, DNA damage assessment through γH2AX analysis, apoptosis evaluation through acridine-orange and ethidium bromide double staining assays, as well as caspase 3 activity measurement using a colorimetric assay. CD151 expression was examined through ELISA, flow cytometry and RT-qPCR.</p><p><strong>Results: </strong>The results showed a significant reduction in TNBC/RR cell viability following co-treatment. Moreover, the co-treatment reduced cell migration, induced apoptosis, downregulated CD151 expression, and increased caspase 3 activity in TNBC/RR cells. Additionally, CD151 was predicted to serve as a therapy response marker for co-treatment with TAU and IR.</p><p><strong>Conclusion: </strong>These findings suggest the potential of combination treatment with IR and TAU as a promising strategy to overcome RT resistance in TNBC. Furthermore, CD151 emerges as a valuable therapy response marker for chemoradiotherapy.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"685-706"},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016470","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}
Pub Date : 2024-11-01Epub Date: 2024-08-21DOI: 10.1007/s00280-024-04710-3
Vassilios Aslanis, Khalid Abd-Elaziz, Robert J Slack, Anne Brinch, Lise Gravelle, Wayne Morley, De Phung, Kimberly Herman, Ian Holyer, Karen Killerup Poulsen, Peter Dogterom, Susan Tantawi, Fredrik R Zetterberg, Brian Jacoby, Hans Schambye, Bertil Lindmark
Purpose: Overexpression of galectin-3, a β-galactoside-binding lectin, is associated with fibrotic diseases and cancer. Selvigaltin is an oral galectin-3 inhibitor, previously administered as a 50 mg capsule. This study aimed to evaluate the relative bioavailability and food effect of selvigaltin as a 100 mg tablet in healthy volunteers.
Methods: In this single-dose, randomized, three-period, crossover study (GALBA-1; NCT05747573), participants received selvigaltin as a 100 mg tablet (under fasted and fed conditions) or as two 50 mg capsules (under fasted conditions). Primary endpoints included plasma and urine pharmacokinetic (PK) parameters. Secondary endpoints were safety and tolerability.
Results: Of the 13 enrolled participants, 12 completed the study. Under fasted conditions, geometric mean maximum observed plasma concentration (Cmax) and systemic exposure (AUC0─inf) of selvigaltin were 161.0% and 84.0% higher, respectively, after administration of a tablet vs. capsules. Under fed vs. fasted conditions, geometric mean Cmax of the selvigaltin tablet was 20.0% lower, whereas AUC0─inf was unaffected. Geometric mean percentage of total dose of selvigaltin excreted in urine over 0─96 h was 30.3% and 35.9% for the tablet under fasted and fed conditions, respectively, and 14.5% for the capsules. No treatment-emergent severe or serious adverse events or study discontinuations due to a treatment-emergent adverse event were reported.
Conclusion: The tablet formulation of selvigaltin displayed higher bioavailability vs. the capsule formulation, with minimal effect of food on PK. Selvigaltin was well-tolerated during all treatments. These findings warrant further clinical development of the tablet formulation of selvigaltin without specific food restrictions.
Clinical trial registration: NCT05747573; February 28, 2023.
{"title":"Relative bioavailability and food effect of the galectin-3 inhibitor selvigaltin (GB1211) administered as a tablet in healthy participants (GALBA-1).","authors":"Vassilios Aslanis, Khalid Abd-Elaziz, Robert J Slack, Anne Brinch, Lise Gravelle, Wayne Morley, De Phung, Kimberly Herman, Ian Holyer, Karen Killerup Poulsen, Peter Dogterom, Susan Tantawi, Fredrik R Zetterberg, Brian Jacoby, Hans Schambye, Bertil Lindmark","doi":"10.1007/s00280-024-04710-3","DOIUrl":"10.1007/s00280-024-04710-3","url":null,"abstract":"<p><strong>Purpose: </strong>Overexpression of galectin-3, a β-galactoside-binding lectin, is associated with fibrotic diseases and cancer. Selvigaltin is an oral galectin-3 inhibitor, previously administered as a 50 mg capsule. This study aimed to evaluate the relative bioavailability and food effect of selvigaltin as a 100 mg tablet in healthy volunteers.</p><p><strong>Methods: </strong>In this single-dose, randomized, three-period, crossover study (GALBA-1; NCT05747573), participants received selvigaltin as a 100 mg tablet (under fasted and fed conditions) or as two 50 mg capsules (under fasted conditions). Primary endpoints included plasma and urine pharmacokinetic (PK) parameters. Secondary endpoints were safety and tolerability.</p><p><strong>Results: </strong>Of the 13 enrolled participants, 12 completed the study. Under fasted conditions, geometric mean maximum observed plasma concentration (C<sub>max</sub>) and systemic exposure (AUC<sub>0─inf</sub>) of selvigaltin were 161.0% and 84.0% higher, respectively, after administration of a tablet vs. capsules. Under fed vs. fasted conditions, geometric mean C<sub>max</sub> of the selvigaltin tablet was 20.0% lower, whereas AUC<sub>0─inf</sub> was unaffected. Geometric mean percentage of total dose of selvigaltin excreted in urine over 0─96 h was 30.3% and 35.9% for the tablet under fasted and fed conditions, respectively, and 14.5% for the capsules. No treatment-emergent severe or serious adverse events or study discontinuations due to a treatment-emergent adverse event were reported.</p><p><strong>Conclusion: </strong>The tablet formulation of selvigaltin displayed higher bioavailability vs. the capsule formulation, with minimal effect of food on PK. Selvigaltin was well-tolerated during all treatments. These findings warrant further clinical development of the tablet formulation of selvigaltin without specific food restrictions.</p><p><strong>Clinical trial registration: </strong>NCT05747573; February 28, 2023.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"707-720"},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016471","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}
Purpose: 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 14C-radiolabeled envonalkib in healthy Chinese male subjects.
Methods: A single oral dose of 600 mg (150 µCi) [14C]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.
Results: After dosing, the median Tmax of radioactivity was 4 h and the mean t1/2 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.
Conclusion: Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.
{"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}
Pub Date : 2024-11-01Epub Date: 2024-08-05DOI: 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
Background: 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).
Methods: 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.
Results: 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.
Conclusion: 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.
{"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}
Purpose: 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.
Methods: 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.
Results: 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 Cmax and AUC0-t 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.
Conclusion: 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.
{"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}