Cancer Chemotherapy and Pharmacology最新文献

{"title":"Influence of CYP2C8*3 and ABCG2 C421A genetic polymorphisms on trough concentration and molecular response of imatinib in Egyptian patients with chronic myeloid leukemia.","authors":"Safwat A Mangoura, Mahmoud H Abdel-Raheem, Hanan A Eltyb, Mohammed S Molla, Abeer M R Hussein","doi":"10.1007/s00280-024-04723-y","DOIUrl":"10.1007/s00280-024-04723-y","url":null,"abstract":"<p><strong>Purpose: </strong>The treatment landscape for chronic myeloid leukemia (CML) has been revolutionized by the introduction of imatinib, a tyrosine kinase inhibitor, which has transformed the disease from a fatal condition into a manageable chronic illness for a substantial number of patients. Despite this, some individuals do not respond adequately to the treatment, and others may experience disease progression even with continued therapy. This study examined how CYP2C8*3 (G416A; rs11572080) and ABCG2 C421A (rs2231142) single nucleotide polymorphisms (SNPs) affect the plasma trough concentration and therapeutic response of imatinib in Egyptian CML patients.</p><p><strong>Methods: </strong>The study included fifty patients with chronic-phase CML, who were categorized into two groups: responders (n = 26) and non-responders (n = 24), according to their BCR-ABL1 transcription levels after 12 months of imatinib treatment. Genotyping of the CYP2C8*3 and ABCG2 C421A polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), while plasma trough concentrations were determined through high-performance liquid chromatography with ultraviolet-diode array detection (HPLC-UV/DAD).</p><p><strong>Results: </strong>Patients with the CA genotype of ABCG2 C421A showed significantly higher mean plasma trough concentrations of imatinib (CA: 1731 ± 424.7 ng/mL; CC: 1294 ± 381.3 ng/mL; p = 0.0132) and demonstrated a better molecular response compared to those with the CC genotype (p = 0.0395).</p><p><strong>Conclusion: </strong>The ABCG2 C421A polymorphism significantly influenced imatinib plasma trough concentrations and molecular responses in Egyptian chronic-phase CML patients. Genotyping of this polymorphism in these patients could assist in optimizing imatinib therapy, predicting more favorable treatment outcomes, and enabling the development of more personalized treatment plans.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"12"},"PeriodicalIF":2.7,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876232","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}

{"title":"Plasma clearance of 5-fluorouracil is more influenced by variations in glomerular filtration rate than by uracil concentration.","authors":"Alice Matheux, Laurine Collas, Maelle Grisard, Léa Goulaieff, François Ghiringhelli, Leïla Bengrine-Lefevre, Julie Vincent, Francoise Goirand, Bernard Royer, Antonin Schmitt","doi":"10.1007/s00280-024-04732-x","DOIUrl":"https://doi.org/10.1007/s00280-024-04732-x","url":null,"abstract":"<p><strong>Objectives: </strong>The use of plasma uracil measurements to detect dihydropyrimidine dehydrogenase (DPD) deficiency is one of the methods for preventing toxicities associated with fluoropyrimidines, including 5-Fluorouracil (5-FU). Unfortunately, this measurement is subject to variations, that may lead to unnecessary dosage reductions and therefore to a reduced efficacy of treatment. Recently, new factors such as hepatic and renal impairment have been proposed as also influencing uracil concentration. The aim of our study was therefore to study the influence of renal or hepatic function on 5-FU clearance.</p><p><strong>Patients and methods: </strong>This was a retrospective study, using patients treated with 5-FU between September 1, 2018 to December 1, 2022 in a French Clinical Cancer Center. Patients were included after treatment with 5FU and therapeutic monitoring of 5FU concentrations after each course of chemotherapy. For each patient, DPD phenotyping by uracil concentration measurement was determined before the first course of 5FU. Blood samples were then taken the day after the start of the 5-FU infusion, between 8 and 10 am, for the first three cycles of 5-FU. With the exception of uracil concentration, which was determined only once, the various data were recorded for each course of 5FU chemotherapy performed. Patients with incomplete information (missing one of the above parameters) were excluded from the database.</p><p><strong>Results: </strong>We included 227 patients, corresponding to 227 uracil concentrations and 575 5-FU concentrations. In an original development, our results show for the first time that 5-FU clearance was proportionally correlated with eGFR (calculated according to CKD-EPI formula). Although we failed to demonstrate this hypothesis significantly, we observed that 5-FU clearance may be more dependent on eGFR than on uracil concentration for low uracil concentrations values.</p><p><strong>Conclusion: </strong>Our study reinforces the still poorly accepted idea of the value of focusing on eGFR in 5-FU dose adjustment.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"9"},"PeriodicalIF":2.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863452","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}

{"title":"Absorption, single-dose and steady-state metabolism, excretion, and pharmacokinetics of adagrasib, a KRAS^G12C inhibitor.","authors":"Lisa Rahbaek, Cornelius Cilliers, Christopher J Wegerski, Natalie Nguyen, Jennifer Otten, Lauren Hargis, Matthew A Marx, James G Christensen, Jonathan Q Tran","doi":"10.1007/s00280-024-04728-7","DOIUrl":"https://doi.org/10.1007/s00280-024-04728-7","url":null,"abstract":"<p><strong>Objective: </strong>This study investigated absorption, metabolism, and excretion of adagrasib after a single oral 600 mg dose (1 µCi [¹⁴C]-adagrasib) in 7 healthy subjects and compared the metabolite profile to the profile at steady-state in 4 patients dosed at 600 mg twice daily.</p><p><strong>Methods: </strong>Plasma, urine, and feces were collected post [¹⁴C]-adagrasib administration and total radioactivity and pooled sample metabolite profiles were determined. Adagrasib pharmacokinetics were determined in plasma and urine. The steady-state plasma metabolite profile was examined in patients and in vitro studies were performed to understand adagrasib's potential to inhibit CYP enzymes and identify CYPs involved in its metabolism.</p><p><strong>Results: </strong>The total mean recovery of the administered radioactivity was 79.2%, with 74.7% and 4.49% of total radioactivity recovered from feces and urine, respectively. Only 1.8% of the dose was excreted in urine as unchanged adagrasib, indicating negligible renal clearance. Adagrasib, M55a, M11, and M68 were major plasma components accounting for 38.3%, 13.6%, 13.4%, and 11.0% of the total plasma radioactivity exposure, respectively. Metabolite M55a was not detected in plasma at steady state where only M68 (24%) and M11 (17.1%) were abundant. In vitro data showed that CYP3A4 (72%) and CYP2C8 (28%) are main contributors to metabolism and adagrasib is a time-dependent inhibitor of CYP3A4.</p><p><strong>Conclusion: </strong>Elimination of adagrasib is mainly by fecal excretion. Adagrasibs altered metabolite profile at steady state is likely due to CYP3A4 autoinhibition. The abundant steady-state plasma metabolites, M68 and M11, are not human specific and do not contribute significantly to the pharmacological activity of adagrasib.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"7"},"PeriodicalIF":2.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852945","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}

{"title":"Predictive factors for first dose reduction and interruption of lenvatinib after beginning of the standard dose in Japanese patients with thyroid cancer.","authors":"Kazuma Fujita, Mitsuji Nagahama, Akifumi Suzuki, Chie Masaki, Kiminori Sugino, Koichi Ito, Masatomo Miura","doi":"10.1007/s00280-024-04729-6","DOIUrl":"10.1007/s00280-024-04729-6","url":null,"abstract":"<p><strong>Purpose: </strong>The associations between first dose reduction or interruption by side effects and lenvatinib plasma trough concentration (C₀) after administration of a starting dose of 24 mg in 70 Japanese patients with thyroid cancer were evaluated.</p><p><strong>Methods: </strong>Plasma samples were collected each week for 1 month and at the first incidence of side effects leading to dose reduction or interruption after beginning administration of 24 mg lenvatinib.</p><p><strong>Results: </strong>The area under the receiver operating characteristic curve was 0.789 at a lenvatinib C₀ threshold of 128.25 ng/mL for predicting the first dose reduction or interruption. The median time to the first dose reduction or interruption was 14.0 days in patients with a C₀ of ≥ 128.25 ng/mL and 21.0 days in those with a C₀ of < 128.25 ng/mL (P = 0.001). At one, two, three and four weeks respectively, the first dose reduction or interruption was associated with body weight (P = 0.034); sex (P = 0.021); sex, age, and lenvatinib C₀ of ≥ 128.25 ng/mL (P = 0.025, 0.024, and 0.048, respectively); and age and lenvatinib C₀ of ≥ 128.25 ng/mL (each P = 0.004).</p><p><strong>Conclusions: </strong>On day 8 after administration of 24 mg lenvatinib, lenvatinib dose may be adjusted based on the target C₀ of 128.25 ng/mL to maintain a high dose intensity during this early phase; however, because persistence of a higher C₀ of 128.25 ng/mL causes early dose interruption or reduction, prospective dose reduction based on the next lower target C₀ for the maintenance phase may be necessary.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"8"},"PeriodicalIF":2.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863461","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}

{"title":"Intrathecal pemetrexed for leptomeningeal metastases in a patient with ALK-rearranged lung adenocarcinoma: a case report.","authors":"Emelie Gezelius, Maria Planck, Bassam Hazem, Seema Nagpal, Heather Wakelee","doi":"10.1007/s00280-024-04735-8","DOIUrl":"10.1007/s00280-024-04735-8","url":null,"abstract":"<p><p>Progressive leptomeningeal metastases (LM) are associated with intractable neurological symptoms and a poor prognosis, and effective treatment options are limited. Intrathecal (IT) pemetrexed has been shown to confer clinical benefit in lung adenocarcinoma, yet our understanding of the efficacy and safety of the treatment is limited. We report a patient with a long-standing history of leptomeningeal disease due to ALK-positive adenocarcinoma of the lung, previously controlled by increased doses of lorlatinib (125 mg/day). Rapid LM progression prompted the start of IT pemetrexed, after which the patient experienced immediate clinical improvement. The case provides additional support that IT pemetrexed can offer symptomatic relief and may be considered as a treatment option in advanced LM. Furthermore, the case illustrates that an increased dose of lorlatinib may efficiently control LM in patients with ALK-rearranged NSCLC, following progression on standard lorlatinib dosage.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"6"},"PeriodicalIF":2.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833917","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}

{"title":"Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892).","authors":"Sarah E Taylor, Sarah Behr, Kristine L Cooper, Haider Mahdi, Denise Fabian, Holly Gallion, Frederick Ueland, John Vargo, Brian Orr, Eugenia Girda, Madeleine Courtney-Brooks, Alexander B Olawaiye, Leslie M Randall, Debra L Richardson, Stephanie A Sullivan, Marilyn Huang, Susan M Christner, Sushil Beriwal, Yan Lin, Aman Chauhan, Edward Chu, Elise C Kohn, Charles Kunos, S Percy Ivy, Jan H Beumer","doi":"10.1007/s00280-024-04720-1","DOIUrl":"10.1007/s00280-024-04720-1","url":null,"abstract":"<p><strong>Background: </strong>The addition of IV triapine to chemoradiation appeared active in phase I and II studies but drug delivery is cumbersome. We examined PO triapine with cisplatin chemoradiation.</p><p><strong>Methods: </strong>We implemented a 3 + 3 design for PO triapine dose escalation with expansion, starting at 100 mg, five days a week for five weeks while receiving radiation with weekly IV cisplatin for locally advanced cervical or vaginal cancer. Maximum tolerated dose (MTD), dose limiting toxicity (DLT), adverse events, pharmacokinetics (PK), pharmacodynamics (PD), and metabolic complete response (mCR) were assessed.</p><p><strong>Results: </strong>19/21 patients were DLT evaluable. DLTs included grade 4 neutropenia (n = 2), leukopenia (n = 2), lymphopenia (n = 2), and hypokalemia (n = 1). Grade 3 toxicities at least possibly related were as expected for cisplatin chemoradiation: lymphopenia (n = 12), anemia (n = 10), neutropenia (n = 4), leukopenia (n = 8), decreased platelets (n = 2), hypertension (n = 1), and hyponatremia (n = 1). MTD and RP2D were established at 100 mg. 8/13 evaluable patients had a mCR. Triapine had a bioavailability of 59%. Methemoglobin levels correlated with triapine exposure. Smoking almost doubled CYP1A2 mediated triapine clearance.</p><p><strong>Conclusions: </strong>Oral triapine is safe when given with cisplatin chemoradiation, convenient, bioavailable. Exposure is negatively impacted by smoking, and methemoglobin is a biomarker of exposure.</p><p><strong>Clinical trial registration: </strong>NCT02595879.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"4"},"PeriodicalIF":2.7,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823869","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}

{"title":"Absorption, metabolism, and excretion of oral [¹⁴C] radiolabeled donafenib: an open-label, phase I, single-dose study in humans.","authors":"Sheng Ma, Ling Yi, YiCong Bian, Binhua Lv, Cong Zhang, Chengwei Li, Hua Zhang, Liyan Miao","doi":"10.1007/s00280-024-04725-w","DOIUrl":"10.1007/s00280-024-04725-w","url":null,"abstract":"<p><strong>Purpose: </strong>The study aims to investigate the absorption, metabolism, and excretion of donafenib, a deuterated derivative of sorafenib, in healthy Chinese male volunteers.</p><p><strong>Methods: </strong>Six healthy Chinese male volunteers were administered a single oral dose of 300 mg donafenib containing 120 µCi of [14 C]-donafenib. The study involved collecting and analyzing plasma, urine, and feces samples to determine the recovery and distribution of total radioactivity, identify metabolites, and assess the metabolic pathways of donafenib.</p><p><strong>Results: </strong>The mean recovery of total radioactivity was 97.31% of the administered dose. Six metabolites were identified, with the parent drug being the major radioactive component in plasma (67.52% of total radioactivity) and feces (83.17% of the dose). The N-oxidation metabolite (M2) was prominent in plasma. Donafenib was predominantly excreted via feces, indicating liver metabolism, with minimal renal excretion. The metabolic pathways of donafenib were similar to those of sorafenib, but the metabolite profiles differed significantly. Notably, the amide hydrolysis metabolite M6, present in sorafenib, was absent in donafenib.</p><p><strong>Conclusion: </strong>Donafenib is primarily metabolized in the liver and excreted through feces, with a metabolic profile that differs from sorafenib due to the deuterium isotope effect. These differences in metabolic characteristics may contribute to donafenib's improved safety and efficacy as a treatment for advanced hepatocellular carcinoma (HCC).</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"5"},"PeriodicalIF":2.7,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823867","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}

{"title":"Sulforaphane inhibits multiple myeloma cell-induced osteoclast differentiation and macrophage proliferation by elevating ferroportin1.","authors":"Weichu Sun, Jingqi Sun, Wei Hu, Cong Luo, Zhongwei Lu, Fen He, Hongyan Zhao, Xi Zeng, Deliang Cao, Junjun Li, Chang Zhang, Jiliang Xia","doi":"10.1007/s00280-024-04736-7","DOIUrl":"https://doi.org/10.1007/s00280-024-04736-7","url":null,"abstract":"<p><strong>Purpose: </strong>Osteolysis is a common complication in patients with multiple myeloma (MM). Our previous studies have demonstrated that MM cells can promote osteoclast differentiation of macrophages. In this study, we explored the effect of sulforaphane (SFN), a natural NRF2 activator found in broccoli, on MM cell-induced osteoclast differentiation.</p><p><strong>Methods: </strong>Conditional medium (CM) derived from MM cells was used to induce osteoclast differentiation, and TRAP staining was performed to examine osteoclast. Gene expression was detected by western blotting or real-time PCR. Cell counting and EdU staining were performed to test macrophage proliferation.</p><p><strong>Results: </strong>We showed that the CM of MM cells downregulated the expression of ferroportin1 (Fpn1), the only known iron exporter in vertebrate cells, thereby increasing cellular iron levels in murine macrophage cells RAW264.7. Deferoxamine (DFO), an iron chelator, effectively blocked MM cell CM-induced osteoclast differentiation and macrophage proliferation, suggesting that iron overload played a key role in these cellular events. Subsequent mechanistic investigations revealed that MM cell CM induced osteoclast differentiation and macrophage proliferation by activating the JNK/AP-1/NFATC1 pathway and PI3K/AKT pathway. SFN was found to increase Fpn1 expression, leading to decreased cellular iron levels in RAW264.7 cells activated by MM cell CM. Importantly, the osteoclast differentiation and macrophage proliferation induced by MM cell CM were significantly inhibited by SFN.</p><p><strong>Conclusion: </strong>Altogether, our findings indicated that SFN inhibits MM cell-induced osteoclast differentiation and macrophage proliferation by elevating FPN1 levels. SFN could be a promising therapeutic strategy for MM-associated osteolysis.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"3"},"PeriodicalIF":2.7,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805874","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}

{"title":"Influence of DPYD gene polymorphisms on 5-Fluorouracil toxicities in Thai colorectal cancer patients.","authors":"Chalirmporn Atasilp, Natchaya Vanwong, Pavitchaya Yodwongjane, Phichai Chansriwong, Ekaphop Sirachainan, Thanyanan Reungwetwattana, Pimonpan Jinda, Somthawin Aiempradit, Suwannee Sirilerttrakul, Monpat Chamnanphon, Apichaya Puangpetch, Nipaporn Sankuntaw, Patompong Satapornpong, Thomas Fabienne, Chonlaphat Sukasem","doi":"10.1007/s00280-024-04722-z","DOIUrl":"10.1007/s00280-024-04722-z","url":null,"abstract":"<p><p>DPYD polymorphisms have been widely found to be related to 5-FU-induced toxicities. The aim of this study was to establish significant associations between five single-nucleotide polymorphisms of DPYD and 5-FU hematological toxicities in Thai colorectal cancer patients. The toxicities were analyzed at the first and second cycles of 5-FU administration in 75 patients. Genotyping was performed using TaqMan real-time PCR. The genotype frequencies of DPYD*2A,1905 + 1 G > A and DPYD 1774 C > T were all wild type. The frequencies of genetic testing for DPYD*5, 1627 A > G, DPYD 1896T > C, and DPYD*9A, 85 A > G were 37.30% (AG; 34.60%, GG; 2.70%), 32.00% (TC; 25.30%, CC; 6.70%), and 13.40% (AG; 10.70%, GG; 2.70%), respectively. The results reveal significant findings with neutropenia occurring in 100% (2/2) of the patients with homozygous variant DPYD*9A (GG) from the first cycle of treatment for both Grade 1-4 and Grade 3-4 toxicities (P = 0.003 and P < 0.001 respectively). DPYD *9A was related to Grade 1-4 leukopenia (P = 0.001) and both Grade 1-4 and severe thrombocytopenia (P < 0.001 and P < 0.001) in the first cycle. In the second cycle, DPYD*5 was shown to be closely associated with no Grade 1-4 toxicity (P = 0.02). However, we found that 100% (2/2) of patients carrying the homozygous variant (GG) DPYD*5, presented no significant toxicity, so, DPYD*5 may be a predictive marker of neutropenia in patients treated with 5-FU. These outcomes suggest that there may be an increased risk of developing 5-FU-induced neutropenia in patients carrying the DPYD*9A, which should be considered as part of the standard procedure.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"2"},"PeriodicalIF":2.7,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799502","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}

{"title":"Pharmacokinetic analysis of crushed venetoclax tablets combined with azacitizine for recurrent pediatric acute myeloid leukemia (AML).","authors":"Motohiro Matsui, Takeo Yasu, Atsushi Makimoto, Yuki Yuza","doi":"10.1007/s00280-024-04730-z","DOIUrl":"10.1007/s00280-024-04730-z","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of a combination therapy consisting of venetoclax (VEN) and azacytidine (AZA) for newly diagnosed acute myeloid leukemia (AML) has been confirmed in elderly patients. However, the clinical data on VEN for pediatric AML are limited. A combination therapy consisting of crushed VEN tablets and AZA (VEN/AZA) was administered to two children with recurrent AML. The pharmacokinetics of VEN were then analysed.</p><p><strong>Case presentation: </strong>[Patient 1] A 1-year-old, male patient who experienced an AML relapse following an allogeneic hematopoietic stem cell transplantation received three courses of VEN/AZA. At the initial dosage of VEN (8 mg/kg), the minimum plasma concentration (C_min) was only 0.44 µg/ml, which was far less than the optimal C_min of 1.2 µg/ml. Subsequent dose-escalation to 10 mg/kg only achieved C_min 0.42 µg/ml. [Patient 2] A 3-year-old, female patient in whom infantile acute lymphoblastic leukemia was originally diagnosed experienced a recurrence in the form of AML after lineage-switching. Three courses of VEN/AZA were administered with the same therapeutic drug monitoring as in Case 1. The C_min of VEN was 0.15 µg/ml at 8 mg/kg. Afterwards, voriconazole 16 mg/kg/day was begun for a concomitant fungal infection together with VEN 2 mg/kg. This combination finally achieved C_min 1.14 µg/ml probably through CYP3A4 inhibition by voriconazole. In terms of safety, only grade 4 hematological adverse events were observed in both patients. In terms of efficacy, patient 1 and patient 2 achieved stable disease status for two months and six months, respectively.</p><p><strong>Conclusion: </strong>Pediatric patients may scarcely achieve effective plasma concentration of VEN when crushed tablets are used at the same dosage as in adults.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"1"},"PeriodicalIF":2.7,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791109","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}