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A first-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors. TAS-117 是一种异位 AKT 抑制剂,对晚期实体瘤患者进行了首次人体 I 期研究。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-02-27 DOI: 10.1007/s00280-023-04631-7
Toshihiko Doi, Shunji Takahashi, Daisuke Aoki, Kan Yonemori, Hiroki Hara, Kosei Hasegawa, Kazuhiro Takehara, Kenichi Harano, Mayu Yunokawa, Hiroyuki Nomura, Tatsunori Shimoi, Koji Horie, Aiko Ogasawara, Shinichi Okame

Purpose: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated.

Methods: This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity.

Results: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response.

Conclusion: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition.

Trial registration: jRCT2080222728 (January 29, 2015).

目的:TAS-117 是一种高效、选择性口服异构泛 AKT 抑制剂,正在开发用于晚期/转移性实体瘤的治疗。该研究对其安全性、临床药理学、药物基因组学和疗效进行了调查:这项I期、开放标签、非随机、剂量递增、首次人体试验研究招募了晚期/转移性实体瘤患者,包括三个阶段(剂量递增阶段[DEP]、方案调整阶段[RMP]和安全性评估阶段[SAP])。SAP 的剂量和治疗方案在 DEP 和 RMP 中确定。研究了每日一次给药和间歇给药(服药 4 天/停药 3 天,21 天为一个周期)。主要终点是 DEP 和 RMP 第一周期的剂量限制性毒性(DLT)以及 SAP 的不良事件(AE)和药物不良反应(ADR)发生率。次要终点包括药代动力学、药效学、药物基因组学和抗肿瘤活性:在66名入组患者中,65人接受了TAS-117治疗(DEP,12人;RMP,10人;SAP,43人)。24毫克/天的间歇给药剂量未出现DLT,该剂量被选为SAP的推荐剂量。在 SAP 中,98.5% 的患者同时出现 AE 和 ADR(等级≥3,分别为 67.7% 和 60.0%)。在测试的剂量范围内(8 至 32 毫克/天),TAS-117 的药代动力学与剂量成正比,药效学分析表明磷酸化 PRAS40(AKT 的直接底物)减少。SAP中的4名患者已证实有部分反应:结论:TAS-117的口服剂量为每天一次至16毫克,间歇剂量为每天24毫克,耐受性良好。在所评估的剂量下,TAS-117的药代动力学与剂量成正比。抗肿瘤活性可能是通过抑制AKT产生的。试验注册:jRCT2080222728(2015年1月29日)。
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引用次数: 0
Azithromycin in cancer treatment: envisioning the probable link of mitochondrial dysfunction and necroptosis. 阿奇霉素在癌症治疗中的应用:设想线粒体功能障碍与坏死下垂的可能联系。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2023-11-14 DOI: 10.1007/s00280-023-04617-5
Siti Nazihahasma Hassan, Farizan Ahmad
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引用次数: 0
Doxorubicin concentrations in bone tumour-relevant tissues after bolus and continuous infusion: a randomized porcine microdialysis study. 注射和持续输注后骨肿瘤相关组织中的多柔比星浓度:一项随机猪微量透析研究。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-02-08 DOI: 10.1007/s00280-023-04637-1
Andrea René Jørgensen, Mats Bue, Pelle Hanberg, Elisabeth Krogsgaard Petersen, Christina Harlev, Jakob Hansen, Thomas Baad-Hansen, Akmal Safwat, Maiken Stilling

Purpose: Doxorubicin is a widely used chemotherapeutic drug that can be administered intravenously as both a bolus infusion and a continuous infusion. The latter is believed to lower the risk of cardiotoxicity, which is a critical long-term complication of doxorubicin treatment. The local tissue concentrations of doxorubicin will be reflected in both treatment efficacy and toxicity, but very limited information is available. The aim of this study was to measure the concentration of doxorubicin after continuous and bolus infusion in tissue compartments around a typical location of a bone tumour.

Methods: Sixteen pigs (female, Danish Landrace, mean weight 77 kg) were randomized into two groups of eight. Both groups received an intravenous infusion of 150 mg doxorubicin; Group 1 received a bolus infusion (10-15 min) and Group 2 received a continuous infusion (6 h). Before infusion, microdialysis catheters were placed intravenously and in four bone tumour-relevant tissue compartments (cancellous bone, subcutaneous tissue, synovial fluid of the knee joint and muscle tissue). Sampling was done (n = 15) over 24 h, and venous blood samples were collected as a reference.

Results: Area under the concentration-time curve (AUC0-24 h) for plasma (total concentration) was significantly different between the two groups, while peak drug concentration (Cmax) was significantly higher in two compartments (plasma and synovial fluid of the knee joint) in Group 1 compared to Group 2. Overall, the unbound tissue concentrations were extremely low with values below 0.20 µg/mL.

Conclusion: The pharmacokinetic profile for doxorubicin in the investigated tissues is very similar when comparing bolus and 6 h continuous infusion.

目的:多柔比星是一种广泛使用的化疗药物,可通过静脉注射和持续输注两种方式给药。后者被认为可降低心脏毒性的风险,而心脏毒性是多柔比星治疗的一个重要的长期并发症。多柔比星的局部组织浓度将反映在治疗效果和毒性上,但目前可用的信息非常有限。本研究的目的是测量连续输注和栓剂输注后多柔比星在骨肿瘤典型部位周围组织分区中的浓度:将 16 头猪(雌性,丹麦陆地种,平均体重 77 千克)随机分为两组,每组 8 头。两组均接受 150 毫克多柔比星的静脉输注;第一组接受栓剂输注(10-15 分钟),第二组接受连续输注(6 小时)。输注前,在静脉内和四个骨肿瘤相关组织区(松质骨、皮下组织、膝关节滑液和肌肉组织)放置微透析导管。在 24 小时内进行采样(n = 15),并采集静脉血样本作为参考:结果:血浆浓度曲线下面积(AUC0-24 h)(总浓度)在两组之间存在显著差异,而与第二组相比,第一组两个区段(血浆和膝关节滑液)的峰值药物浓度(Cmax)明显更高。总体而言,未结合的组织浓度极低,低于 0.20 微克/毫升:结论:多柔比星在研究组织中的药代动力学特征与栓剂注射和 6 小时连续输注非常相似。
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引用次数: 0
Using maximum plasma concentration (Cmax) to personalize taxane treatment and reduce toxicity. 利用最大血浆浓度(Cmax)进行个性化的紫杉类药物治疗并降低毒性。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-05-11 DOI: 10.1007/s00280-024-04677-1
Yuchen Sun, Yue Cheng, Daniel L Hertz

Taxanes are a widely used class of anticancer agents that play a vital role in the treatment of a variety of cancers. However, toxicity remains a major concern of using taxane drugs as some toxicities are highly prevalent, they can not only adversely affect patient prognosis but also compromise the overall treatment plan. Among all kinds of factors that associated with taxane toxicity, taxane exposure has been extensively studied, with different pharmacokinetic (PK) parameters being used as toxicity predictors. Compared to other widely used predictors such as the area under the drug plasma concentration curve versus time (AUC) and time above threshold plasma drug concentration, maximum plasma concentration (Cmax) is easier to collect and shows promise for use in clinical practice. In this article, we review the previous research on using Cmax to predict taxane treatment outcomes. While Cmax and toxicity have been extensively studied, research on the relationship between Cmax and efficacy is lacking. Most of the articles find a positive relationship between Cmax and toxicity but several articles have contradictory findings. Future clinical trials are needed to validate the relationship between Cmax and treatment outcome and determine whether Cmax can serve as a useful surrogate endpoint of taxane treatment efficacy.

紫杉类药物是一类广泛使用的抗癌药物,在治疗多种癌症中发挥着重要作用。然而,毒性仍然是使用紫杉类药物的一个主要问题,因为一些毒性反应非常普遍,不仅会对患者的预后产生不利影响,还会影响整体治疗计划。在与紫杉类药物毒性相关的各种因素中,紫杉类药物暴露已被广泛研究,不同的药代动力学(PK)参数被用作毒性预测因子。与其他广泛使用的预测指标(如血浆药物浓度曲线下面积与时间的关系(AUC)和血浆药物浓度超过阈值的时间)相比,最大血浆浓度(Cmax)更容易收集,并有望用于临床实践。在本文中,我们回顾了以往利用 Cmax 预测紫杉类药物治疗结果的研究。虽然对 Cmax 和毒性进行了广泛的研究,但缺乏对 Cmax 和疗效之间关系的研究。大多数文章发现Cmax与毒性之间存在正相关关系,但也有几篇文章的研究结果相互矛盾。未来需要进行临床试验来验证 Cmax 与治疗效果之间的关系,并确定 Cmax 是否可作为紫杉类药物疗效的有用替代终点。
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引用次数: 0
Multicenter randomized phase II study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases (YCOG1001). S-1 和奥沙利铂疗法作为结直肠肝转移肝切除术后辅助疗法的多中心随机 II 期研究(YCOG1001)。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-02-19 DOI: 10.1007/s00280-024-04648-6
Mayumi Ozawa, Jun Watanabe, Atsushi Ishibe, Koki Goto, Yoshiro Fujii, Kazuya Nakagawa, Yusuke Suwa, Hirokazu Suwa, Hidenobu Masui, Mitsutaka Sugita, Yasuhisa Mochizuki, Shigeru Yamagishi, Seiji Hasegawa, Yuki Homma, Masashi Momiyama, Takafumi Kumamoto, Ryusei Matsuyama, Kazuhisa Takeda, Masataka Taguri, Itaru Endo

Purpose: The high recurrence rate of colorectal cancer liver metastasis (CRCLM) after surgery remains a crucial problem. However, adjuvant chemotherapy after hepatectomy for CRCLM has not yet been established. This study evaluated the efficacy of adjuvant therapy with S-1 and oxaliplatin (SOX).

Methods: In a multicenter, randomized, phase II study, patients undergoing curative resection of CRCLM were randomly enrolled in a 1:1 ratio to either the low- or high-dose group. S-1 and oxaliplatin were administered from days 1 to 14 of a 3-week cycle as a 2-h infusion every 3 weeks. The dose of S-1 was fixed at 80 mg/m2. The doses in the low- and high-dose oxaliplatin groups were 100 mg/m2 (low-dose group) and 130 mg/m2 (high-dose group), respectively. This treatment was repeated eight times. The primary endpoint was the rate of discontinuation owing to toxicity. The secondary endpoints were the relapse-free survival (RFS) and frequency of adverse events (AEs).

Results: Between August 2010 and March 2015, 44 patients (low-dose group: 31 patients and high-dose group: 13 patients) were enrolled in the study. Of these, one patient was excluded from the efficacy analysis. In the high-dose group, five of nine patients were unable to continue the study due to toxicity in February 2013. At that time, recruitment to the high-dose group was stopped from the protocol. The relative dose intensity (RDI) for S-1 in the low- and high-dose groups were 49.8 and 48.7% (p = 0.712), and that for oxaliplatin was 75.9 and 73.0% (p = 0.528), respectively. The rates of discontinuation due to toxicity were 60 and 53.8% in the low- and high-dose groups, respectively, with no marked difference noted between the groups (p = 0.747). The frequency of grade ≥ 3 common adverse events was neutropenia (23.3%/23.1%), diarrhea (13.3%/15.4%), and peripheral sensory neuropathy (6.7%/7.7%). The disease-free survival (DFS) at 3 years was 52.9% in the low-dose group, which was not significantly different from that in the high-dose group (46.2%; p = 0.705).

Conclusions: SOX regimens as adjuvant therapy after hepatectomy for CRCLM had high rates of discontinuation due to toxicity in both groups. In particular, the RDI of S-1 was < 50%. Therefore, the SOX regimen is not recommended as adjuvant chemotherapy after hepatectomy for CRCLM.

目的:结直肠癌肝转移(CRCLM)术后复发率高仍是一个关键问题。然而,CRCLM 肝切除术后的辅助化疗尚未确立。本研究评估了S-1和奥沙利铂(SOX)辅助治疗的疗效:在一项多中心、随机、II 期研究中,按 1:1 的比例将接受 CRCLM 根治性切除术的患者随机纳入低剂量组或高剂量组。S-1和奥沙利铂在3周周期的第1至14天输注,每3周输注一次,每次2小时。S-1 的剂量固定为 80 毫克/平方米。奥沙利铂低剂量组和高剂量组的剂量分别为100毫克/平方米(低剂量组)和130毫克/平方米(高剂量组)。该治疗重复进行了八次。主要终点是因毒性而停药的比率。次要终点为无复发生存率(RFS)和不良事件发生率(AEs):2010年8月至2015年3月期间,44名患者(低剂量组:31名患者,高剂量组:13名患者)参与了研究。其中,一名患者被排除在疗效分析之外。2013 年 2 月,在高剂量组的 9 名患者中,有 5 人因毒性而无法继续研究。当时,研究方案停止了高剂量组的招募。低剂量组和高剂量组的S-1相对剂量强度(RDI)分别为49.8%和48.7%(P = 0.712),奥沙利铂的相对剂量强度(RDI)分别为75.9%和73.0%(P = 0.528)。低剂量组和高剂量组因毒性而停药的比例分别为60%和53.8%,组间无明显差异(p = 0.747)。常见的≥3级不良反应为中性粒细胞减少(23.3%/23.1%)、腹泻(13.3%/15.4%)和周围感觉神经病变(6.7%/7.7%)。低剂量组的3年无病生存率(DFS)为52.9%,与高剂量组(46.2%;P = 0.705)相比无显著差异:结论:SOX方案作为CRCLM肝切除术后的辅助治疗,在两组中因毒性导致的停药率都很高。特别是,S-1 的 RDI 为
{"title":"Multicenter randomized phase II study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases (YCOG1001).","authors":"Mayumi Ozawa, Jun Watanabe, Atsushi Ishibe, Koki Goto, Yoshiro Fujii, Kazuya Nakagawa, Yusuke Suwa, Hirokazu Suwa, Hidenobu Masui, Mitsutaka Sugita, Yasuhisa Mochizuki, Shigeru Yamagishi, Seiji Hasegawa, Yuki Homma, Masashi Momiyama, Takafumi Kumamoto, Ryusei Matsuyama, Kazuhisa Takeda, Masataka Taguri, Itaru Endo","doi":"10.1007/s00280-024-04648-6","DOIUrl":"10.1007/s00280-024-04648-6","url":null,"abstract":"<p><strong>Purpose: </strong>The high recurrence rate of colorectal cancer liver metastasis (CRCLM) after surgery remains a crucial problem. However, adjuvant chemotherapy after hepatectomy for CRCLM has not yet been established. This study evaluated the efficacy of adjuvant therapy with S-1 and oxaliplatin (SOX).</p><p><strong>Methods: </strong>In a multicenter, randomized, phase II study, patients undergoing curative resection of CRCLM were randomly enrolled in a 1:1 ratio to either the low- or high-dose group. S-1 and oxaliplatin were administered from days 1 to 14 of a 3-week cycle as a 2-h infusion every 3 weeks. The dose of S-1 was fixed at 80 mg/m<sup>2</sup>. The doses in the low- and high-dose oxaliplatin groups were 100 mg/m<sup>2</sup> (low-dose group) and 130 mg/m<sup>2</sup> (high-dose group), respectively. This treatment was repeated eight times. The primary endpoint was the rate of discontinuation owing to toxicity. The secondary endpoints were the relapse-free survival (RFS) and frequency of adverse events (AEs).</p><p><strong>Results: </strong>Between August 2010 and March 2015, 44 patients (low-dose group: 31 patients and high-dose group: 13 patients) were enrolled in the study. Of these, one patient was excluded from the efficacy analysis. In the high-dose group, five of nine patients were unable to continue the study due to toxicity in February 2013. At that time, recruitment to the high-dose group was stopped from the protocol. The relative dose intensity (RDI) for S-1 in the low- and high-dose groups were 49.8 and 48.7% (p = 0.712), and that for oxaliplatin was 75.9 and 73.0% (p = 0.528), respectively. The rates of discontinuation due to toxicity were 60 and 53.8% in the low- and high-dose groups, respectively, with no marked difference noted between the groups (p = 0.747). The frequency of grade ≥ 3 common adverse events was neutropenia (23.3%/23.1%), diarrhea (13.3%/15.4%), and peripheral sensory neuropathy (6.7%/7.7%). The disease-free survival (DFS) at 3 years was 52.9% in the low-dose group, which was not significantly different from that in the high-dose group (46.2%; p = 0.705).</p><p><strong>Conclusions: </strong>SOX regimens as adjuvant therapy after hepatectomy for CRCLM had high rates of discontinuation due to toxicity in both groups. In particular, the RDI of S-1 was < 50%. Therefore, the SOX regimen is not recommended as adjuvant chemotherapy after hepatectomy for CRCLM.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"565-573"},"PeriodicalIF":2.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905146","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
Effect of lithium on chemotherapy-induced neutropenia in Egyptian breast cancer patients; a prospective clinical study. 锂对埃及乳腺癌患者化疗所致中性粒细胞减少症的影响;一项前瞻性临床研究。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-06-01 Epub Date: 2024-02-07 DOI: 10.1007/s00280-023-04620-w
Ahmed O ELKasar, Fatma Z Hussien, Hala E Abdel-Hamied, Ibrahim G Saleh, Elsayed M Mahgoup, Amr A El-Arabey, Adel R Abd-Allah

Purpose: Myelosuppressive chemotherapy-induced neutropenia (CIN) remains a major limitation of cancer treatment efficacy, necessitating very expensive supportive care. Lithium carbonate, an inexpensive drug, can increase the number of neutrophils, possibly providing an efficacious and cost-effective alternative for treating CIN. The aim of this study was to determine whether lithium therapy can attenuate chemotherapy-induced neutropenia and leukopenia in breast cancer patients.

Methods: A total of 50 breast cancer patients were enrolled in this prospective, interventional, randomized, controlled, and single-blind study. The patients were divided into two groups: a control group (group 1, N = 25 patients) and a lithium-treated (treatment) group (group 2, N = 25 patients). Group 1 patients were further subclassified into a non-neutropenic control group (N = 16) and a neutropenic control (N = 9) based on the subsequent development of severe neutropenia, or not. The control group received 4 cycles of doxorubicin or epirubicin plus cyclophosphamide followed by 2 cycles of paclitaxel. The treatment group received the same regimen as the control group as well as oral lithium carbonate throughout the chemotherapy cycles.

Results: The results showed that the absolute neutrophil count (ANC) was increased in the lithium-treated group, while it was markedly reduced in both the non-neutropenic and neutropenic control groups (by 55.56% and 65.42% post-4 chemotherapy cycles, and by 19.57% and 39.90% post-6 cycles, respectively). The same pattern of alterations was observed for the total white blood cell count in both the control and treatment groups. In addition, the incidence and period prevalence were greatly reduced in the lithium-treated group compared to non-neutropenic and neutropenic control groups.

Conclusion: Lithium therapy ameliorated chemotherapy-induced leukopenia and neutropenia in breast cancer patients. This may provide a new strategy for cost-effective treatment of CIN, particularly in Egyptian cancer patients.

目的:骨髓抑制性化疗诱发的中性粒细胞减少症(CIN)仍然是癌症治疗效果的主要限制因素,需要非常昂贵的支持性治疗。碳酸锂是一种廉价药物,可增加中性粒细胞的数量,可能为治疗中性粒细胞减少症提供一种有效且经济的替代方法。本研究旨在确定锂疗法能否减轻乳腺癌患者化疗引起的中性粒细胞减少症和白细胞减少症:这项前瞻性、干预性、随机对照和单盲研究共招募了 50 名乳腺癌患者。患者分为两组:对照组(第 1 组,25 名患者)和锂治疗组(第 2 组,25 名患者)。根据随后是否出现严重中性粒细胞减少症,第一组患者又被分为非中性粒细胞减少症对照组(16 人)和中性粒细胞减少症对照组(9 人)。对照组接受 4 个周期的多柔比星或表柔比星加环磷酰胺治疗,然后接受 2 个周期的紫杉醇治疗。治疗组接受与对照组相同的治疗方案,并在整个化疗周期中口服碳酸锂:结果显示,锂治疗组的绝对中性粒细胞数(ANC)增加,而非中性粒细胞减少组和中性粒细胞减少对照组的绝对中性粒细胞数明显减少(4个化疗周期后分别减少55.56%和65.42%,6个化疗周期后分别减少19.57%和39.90%)。对照组和治疗组的白细胞总数也出现了同样的变化。此外,与非中性粒细胞减少组和中性粒细胞减少对照组相比,锂治疗组的发病率和发病期大大降低:结论:锂疗法可改善乳腺癌患者化疗引起的白细胞减少症和中性粒细胞减少症。结论:锂疗法可改善乳腺癌患者化疗诱发的白细胞减少症和中性粒细胞减少症,这为经济有效地治疗中性粒细胞减少症(尤其是埃及癌症患者)提供了一种新策略。
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引用次数: 0
Retraction Note: Effectiveness and safety of sorafenib for renal cell, hepatocellular and thyroid carcinoma: pooled analysis in patients with renal impairment. 撤稿说明:索拉非尼治疗肾细胞癌、肝细胞癌和甲状腺癌的有效性和安全性:肾功能受损患者的汇总分析。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 DOI: 10.1007/s00280-023-04587-8
Mototsugu Oya, Shuichi Kaneko, Tsuneo Imai, Toshiaki Tsujino, Toshiyuki Sunaya, Yutaka Okayama
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引用次数: 0
Pharmacology and pharmacokinetics of tazemetostat. 他赛莫司他的药理学和药代动力学。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 Epub Date: 2024-03-23 DOI: 10.1007/s00280-024-04658-4
Marco Orleni, Jan H Beumer

Tazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies.

Tazemetostat 是一种新型口服泽斯特同源增强子 2 (EZH2) 选择性抑制剂,于 2020 年获得美国食品药品管理局 (FDA) 批准,用于晚期上皮样肉瘤或复发/难治性 (R/R) EZH2 突变滤泡性淋巴瘤患者。FDA根据2期临床试验得出的客观反应率和反应持续时间加速批准了这些适应症。Tazemetostat能与S-腺苷蛋氨酸(SAM)辅助因子竞争抑制EZH2,降低组蛋白3的三甲基化赖氨酸27(H3K27me3)水平,H3K27me3被认为是药效学标志物。他赛莫司他具有口服生物利用度高、吸收快和与剂量成比例的暴露等特点,与食物或胃酸还原剂同时服用也不会影响其生物利用度。它在组织中的分布很广,但进入中枢神经系统的机会有限。他赛莫司他在肝脏中通过 CYP3A 代谢为 3 种主要的非活性代谢物(M1、M3 和 M5),半衰期短,主要通过粪便排泄。与氟康唑等中度 CYP3A 抑制剂发生药物相互作用,导致 FDA 建议减少 50%的剂量,而他唑美托与强抑制剂/诱导剂联合用药的研究仍在进行中。不建议因肾功能或肝功能障碍而调整剂量。总体而言,他赛莫司他是美国食品药品管理局批准用于癌症治疗的首个同类EZH2抑制剂。目前的临床研究正在评估多种恶性肿瘤患者的联合疗法。
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引用次数: 0
Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study. 伊沃西地尼治疗晚期IDH1突变胆管癌的药代动力学/药效学:ClarIDHy III期研究结果。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 Epub Date: 2024-01-27 DOI: 10.1007/s00280-023-04633-5
Bin Fan, Ghassan K Abou-Alfa, Andrew X Zhu, Shuchi S Pandya, Hongxia Jia, Feng Yin, Camelia Gliser, Zhaowei Hua, Mohammad Hossain, Hua Yang

Purpose: Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population.

Methods: Patients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 - 2, pre-dose and 2 h post-dose on D15 of C1 - 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously.

Results: PK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [Tmax] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease).

Conclusion: Once-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma.

Clinical trial registration: NCT02989857 Registered February 20, 2017.

目的报告III期ClarIDHy研究的药代动力学(PK)/药效学(PD)结果,以及该人群中PK/PD参数与治疗结果之间的关联:突变型异柠檬酸脱氢酶1(mIDH1)晚期胆管癌患者按2:1的比例随机接受伊沃西地尼或匹配的安慰剂治疗。当疾病出现放射学进展时,可从安慰剂交叉使用伊沃西地尼。用于PK/PD分析(次要终点)的血样采集于周期(C)1-2的第1天(D)、C1-2的第15天(D)、C3以后的第1天(D)的用药前和用药后最多4小时。使用液相色谱-串联质谱法测量血浆伊维西尼和D-2-羟基戊二酸(2-HG)。所有临床反应均在之前进行了集中审查:对156例伊伐替尼治疗患者的样本进行了PK/PD分析。单次和多次口服伊沃西地尼后吸收迅速(观察到的最大血浆浓度[Tmax]时间分别为2.63和2.07小时)。伊沃西地尼在C2D1的暴露量高于单次给药后的暴露量,但蓄积量较低。在伊沃西地尼治疗的患者中,平均血浆2-HG浓度从基线时的1108纳克/毫升降至C2D1时的97.7纳克/毫升,接近之前在健康人中观察到的水平。在稳定状态下观察到的平均 2-HG 抑制率为 75.0%。服用安慰剂后血浆中的 2-HG 未见减少。无论最佳总体反应(疾病进展,或部分反应和疾病稳定)如何,伊沃西地尼治疗患者的血浆2-HG均有下降:结论:每日一次的伊沃西地尼500毫克具有良好的PK/PD特征,证明了2-HG降低的作用机制,因此对晚期mIDH1胆管癌患者有积极的疗效:NCT02989857 注册时间:2017年2月20日。
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引用次数: 0
Pharmacokinetic drug-drug interaction between olaparib and apixaban: a case report. 奥拉帕尼与阿哌沙班的药代动力学药物相互作用:一例报告。
IF 3 4区 医学 Q3 ONCOLOGY Pub Date : 2024-05-01 Epub Date: 2023-11-03 DOI: 10.1007/s00280-023-04606-8
M Berge, J S Giraud, S De Percin, A Puszkiel, A Thomas-Schoemann, B Blanchet
{"title":"Pharmacokinetic drug-drug interaction between olaparib and apixaban: a case report.","authors":"M Berge, J S Giraud, S De Percin, A Puszkiel, A Thomas-Schoemann, B Blanchet","doi":"10.1007/s00280-023-04606-8","DOIUrl":"10.1007/s00280-023-04606-8","url":null,"abstract":"","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"519-521"},"PeriodicalIF":3.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71434000","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
期刊
Cancer Chemotherapy and Pharmacology
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