A sensitive and rapid liquid chromatography tandem mass spectrometry(LC-MS/MS)method was established for the quantification of total and unbound concentrations of LY3214996,an extracellular signal-regulated kinase inh...A sensitive and rapid liquid chromatography tandem mass spectrometry(LC-MS/MS)method was established for the quantification of total and unbound concentrations of LY3214996,an extracellular signal-regulated kinase inhibitor;abemaciclib,a cyclin-dependent kinase 4/6 inhibitor;and abemaciclib active metabolites,M2 and M20,in human plasma,brain tumor,and cerebrospinal fluid samples.The method was validated over a concentration range of 0.2e500 nM within a total run time of 3.8 min using isocratic elution on a Kinetex^(TM) F_(5) column.Detection was performed on a Sciex QTRAP 6500t mass spectrometer employing multiple reaction monitoring mode under positive electrospray ionization.The intra-and inter-batch accuracy as well as the precision of the method for all matrices was within ±20% and ≤20% at the lower limit of quantification,and within ±15% and ≤15% for other quality control levels for all analytes.The unbound fractions of drugs and metabolites in spiked and patient samples were determined using an optimized equilibrium dialysis.The validated method was successfully applied in a phase 0/2 clinical trial to assess the central nervous system penetration of LY3214996 and abemaciclib.展开更多
BACKGROUND This case report addresses the dearth of effective therapeutic interventions for central nervous system metastases in patients with HER2-negative breast cancer.It presents a unique case of a woman with estr...BACKGROUND This case report addresses the dearth of effective therapeutic interventions for central nervous system metastases in patients with HER2-negative breast cancer.It presents a unique case of a woman with estrogen receptor-positive,HER2-negative breast cancer who developed brain metastasis.The report highlights her initial favorable response to abemaciclib and letrozole therapy prior to the discon-tinuation due to drug-induced lung damage(DILD).CASE SUMMARY In this comprehensive case summary,we present the clinical course of a woman in her 60s,who 11 years following primary breast cancer surgery,was diagnosed with multiple brain metastases.As a third-line systemic therapy,she underwent treatment with abemaciclib and letrozole.This treatment approach yielded a near-partial response in her metastatic brain lesions.However,abemaciclib adminis-tration ceased due to the emergence of DILD,as confirmed by a computed tomography scan.The DILD improved after 1 mo of cessation.Despite ongoing therapeutic efforts,the patient’s condition progressively deteriorated,ultimately resulting in death due to progression of the brain metastases.CONCLUSION This case underscores the challenge of managing adverse events in responsive brain metastasis patients,given the scarcity of therapeutic options.展开更多
治疗转移性乳腺癌新药甲磺酸阿贝西尼(abemaciclib mesylate)是周期蛋白依赖激酶(CDK)4/6抑制药,由美国礼来公司(Eli Lilly and company)研发,曾用名为Bemaciclib,用于治疗激素受体(HR)阳性(HR+)及人表皮生长因子受体2(HER2)阴性(HER2-)...治疗转移性乳腺癌新药甲磺酸阿贝西尼(abemaciclib mesylate)是周期蛋白依赖激酶(CDK)4/6抑制药,由美国礼来公司(Eli Lilly and company)研发,曾用名为Bemaciclib,用于治疗激素受体(HR)阳性(HR+)及人表皮生长因子受体2(HER2)阴性(HER2-),经内分泌治疗后乳腺癌已进展或转移的成人晚期患者。阿贝西尼于2015年10月9日获得美国食品药品管理局(FDA)突破性疗法的认定,给予在HR+/HER2-乳腺癌患者中优先评审资格,2017年9月28日批准上市,商品名为Verzenio。该文对甲磺酸阿贝西尼的非临床和临床药理毒理学、临床研究、不良反应、适应证、剂量与用法、用药注意事项及知识产权状态和国内外研究进展等进行介绍。展开更多
Abemaciclib (Verzerio<span style="white-space:nowrap;"><sup><span style="font-family:Verdana, Helvetica, Arial;white-space:normal;background-color:#FFFFFF;">®</sup>...Abemaciclib (Verzerio<span style="white-space:nowrap;"><sup><span style="font-family:Verdana, Helvetica, Arial;white-space:normal;background-color:#FFFFFF;">®</sup>) is a cell cycle inhibitor of both CDK4 and CDK6. In 2017, abemaciclib was approved by the Food and Drug Administration (FDA) and, in 2018 by the European Medicines Agency (EMA) for the treatment of postmenopausal women with hormone receptor positive (HR<sup>+</sup>), human epidermal growth factor receptor 2 negative (HER2<sup><span style="white-space:nowrap;"><sup><span style="white-space:nowrap;">−</sup></sup>) advanced breast cancer. In this mini-review, we provide a series of information for respectively their targets and its selectivity, results on preclinical trial, clinical phase I, II and III trials, and some perspectives. We also describe the batch and flow steps used for the synthesis of this cancer drug.展开更多
Background:In the interim analysis of MONARCH plus,adding abemaciclib to endocrine therapy(ET)improved progression-free survival(PFS)and objective response rate(ORR)in predominantly Chinese postmenopausal women with H...Background:In the interim analysis of MONARCH plus,adding abemaciclib to endocrine therapy(ET)improved progression-free survival(PFS)and objective response rate(ORR)in predominantly Chinese postmenopausal women with HR+/HER2-advanced breast cancer(ABC).This study presents the final pre-planned PFS analysis.Methods:In the phase III MONARCH plus study,postmenopausal women in China,India,Brazil,and South Africa with HR+/HER2-ABC without prior systemic therapy in an advanced setting(cohort A)or progression on prior ET(cohort B)were randomized(2:1)to abemaciclib(150 mg twice daily[BID])or placebo plus:anastrozole(1.0 mg/day)or letrozole(2.5 mg/day)(cohort A)or fulvestrant(500 mg on days 1 and 15 of cycle 1 and then on day 1 of each subsequent cycle)(cohort B).The primary endpoint was PFS of cohort A.Secondary endpoints included cohort B PFS(key secondary endpoint),ORR,overall survival(OS),safety,and health-related quality of life(HRQoL).Results:In cohort A(abemaciclib:n=207;placebo:n=99),abemaciclib plus a non-steroidal aromatase inhibitor improved median PFS vs.placebo(28.27 months vs.14.73 months,hazard ratio[HR]:0.476;95%confidence interval[95%CI]:0.348-0.649).In cohort B(abemaciclib:n=104;placebo:n=53),abemaciclib plus fulvestrant improved median PFS vs.placebo(11.41 months vs.5.59 months,HR:0.480;95%CI:0.322-0.715).Abemaciclib numerically improved ORR.Although immature,a trend toward OS benefit with abemaciclib was observed(cohort A:HR:0.893,95%CI:0.553-1.443;cohort B:HR:0.512,95%CI:0.281-0.931).The most frequent grade≥3 adverse events in the abemaciclib arms were neutropenia,leukopenia,anemia(both cohorts),and lymphocytopenia(cohort B).Abemaciclib did not cause clinically meaningful changes in patient-reported global health,functioning,or most symptoms vs.placebo.Conclusions:Abemaciclib plus ET led to improvements in PFS and ORR,a manageable safety profile,and sustained HRQoL,providing clinical benefit without a high toxicity burden or reduced quality of life.展开更多
目的:研究阿贝西利致不良反应的发生规律和特点,为临床安全合理用药提供参考。方法:检索中国知网、万方数据、维普网、PubMed、Web of Science等数据库自建库以来至2024年7月关于阿贝西利发生不良反应的个案报道,并进行统计分析。结果:...目的:研究阿贝西利致不良反应的发生规律和特点,为临床安全合理用药提供参考。方法:检索中国知网、万方数据、维普网、PubMed、Web of Science等数据库自建库以来至2024年7月关于阿贝西利发生不良反应的个案报道,并进行统计分析。结果:共纳入文献34篇,涉及患者35例,其中包括女性31例(88.57%)和男性4例(11.43%),且以60岁以上的患者居多(18例,51.43%)。所患疾病多为乳腺癌(30例,85.71%)。发生不良反应时间为服药后4 d~23个月,主要集中在开始服药6个月内(25例,71.43%),主要累及消化系统、血液系统、呼吸系统、内分泌系统、心血管系统、免疫系统等。其中23例(65.71%)患者采取对症治疗后不良反应症状改善,2例(5.71%)患者因肺损伤治疗无效死亡。可见,阿贝西利存在潜在致死风险。结论:医务工作者应加强对阿贝西利不良反应的防范与监测,确保患者用药安全有效。展开更多
基金funding provided by the Ben and Catherine Ivy Foundation.
文摘A sensitive and rapid liquid chromatography tandem mass spectrometry(LC-MS/MS)method was established for the quantification of total and unbound concentrations of LY3214996,an extracellular signal-regulated kinase inhibitor;abemaciclib,a cyclin-dependent kinase 4/6 inhibitor;and abemaciclib active metabolites,M2 and M20,in human plasma,brain tumor,and cerebrospinal fluid samples.The method was validated over a concentration range of 0.2e500 nM within a total run time of 3.8 min using isocratic elution on a Kinetex^(TM) F_(5) column.Detection was performed on a Sciex QTRAP 6500t mass spectrometer employing multiple reaction monitoring mode under positive electrospray ionization.The intra-and inter-batch accuracy as well as the precision of the method for all matrices was within ±20% and ≤20% at the lower limit of quantification,and within ±15% and ≤15% for other quality control levels for all analytes.The unbound fractions of drugs and metabolites in spiked and patient samples were determined using an optimized equilibrium dialysis.The validated method was successfully applied in a phase 0/2 clinical trial to assess the central nervous system penetration of LY3214996 and abemaciclib.
文摘BACKGROUND This case report addresses the dearth of effective therapeutic interventions for central nervous system metastases in patients with HER2-negative breast cancer.It presents a unique case of a woman with estrogen receptor-positive,HER2-negative breast cancer who developed brain metastasis.The report highlights her initial favorable response to abemaciclib and letrozole therapy prior to the discon-tinuation due to drug-induced lung damage(DILD).CASE SUMMARY In this comprehensive case summary,we present the clinical course of a woman in her 60s,who 11 years following primary breast cancer surgery,was diagnosed with multiple brain metastases.As a third-line systemic therapy,she underwent treatment with abemaciclib and letrozole.This treatment approach yielded a near-partial response in her metastatic brain lesions.However,abemaciclib adminis-tration ceased due to the emergence of DILD,as confirmed by a computed tomography scan.The DILD improved after 1 mo of cessation.Despite ongoing therapeutic efforts,the patient’s condition progressively deteriorated,ultimately resulting in death due to progression of the brain metastases.CONCLUSION This case underscores the challenge of managing adverse events in responsive brain metastasis patients,given the scarcity of therapeutic options.
文摘治疗转移性乳腺癌新药甲磺酸阿贝西尼(abemaciclib mesylate)是周期蛋白依赖激酶(CDK)4/6抑制药,由美国礼来公司(Eli Lilly and company)研发,曾用名为Bemaciclib,用于治疗激素受体(HR)阳性(HR+)及人表皮生长因子受体2(HER2)阴性(HER2-),经内分泌治疗后乳腺癌已进展或转移的成人晚期患者。阿贝西尼于2015年10月9日获得美国食品药品管理局(FDA)突破性疗法的认定,给予在HR+/HER2-乳腺癌患者中优先评审资格,2017年9月28日批准上市,商品名为Verzenio。该文对甲磺酸阿贝西尼的非临床和临床药理毒理学、临床研究、不良反应、适应证、剂量与用法、用药注意事项及知识产权状态和国内外研究进展等进行介绍。
文摘Abemaciclib (Verzerio<span style="white-space:nowrap;"><sup><span style="font-family:Verdana, Helvetica, Arial;white-space:normal;background-color:#FFFFFF;">®</sup>) is a cell cycle inhibitor of both CDK4 and CDK6. In 2017, abemaciclib was approved by the Food and Drug Administration (FDA) and, in 2018 by the European Medicines Agency (EMA) for the treatment of postmenopausal women with hormone receptor positive (HR<sup>+</sup>), human epidermal growth factor receptor 2 negative (HER2<sup><span style="white-space:nowrap;"><sup><span style="white-space:nowrap;">−</sup></sup>) advanced breast cancer. In this mini-review, we provide a series of information for respectively their targets and its selectivity, results on preclinical trial, clinical phase I, II and III trials, and some perspectives. We also describe the batch and flow steps used for the synthesis of this cancer drug.
文摘Background:In the interim analysis of MONARCH plus,adding abemaciclib to endocrine therapy(ET)improved progression-free survival(PFS)and objective response rate(ORR)in predominantly Chinese postmenopausal women with HR+/HER2-advanced breast cancer(ABC).This study presents the final pre-planned PFS analysis.Methods:In the phase III MONARCH plus study,postmenopausal women in China,India,Brazil,and South Africa with HR+/HER2-ABC without prior systemic therapy in an advanced setting(cohort A)or progression on prior ET(cohort B)were randomized(2:1)to abemaciclib(150 mg twice daily[BID])or placebo plus:anastrozole(1.0 mg/day)or letrozole(2.5 mg/day)(cohort A)or fulvestrant(500 mg on days 1 and 15 of cycle 1 and then on day 1 of each subsequent cycle)(cohort B).The primary endpoint was PFS of cohort A.Secondary endpoints included cohort B PFS(key secondary endpoint),ORR,overall survival(OS),safety,and health-related quality of life(HRQoL).Results:In cohort A(abemaciclib:n=207;placebo:n=99),abemaciclib plus a non-steroidal aromatase inhibitor improved median PFS vs.placebo(28.27 months vs.14.73 months,hazard ratio[HR]:0.476;95%confidence interval[95%CI]:0.348-0.649).In cohort B(abemaciclib:n=104;placebo:n=53),abemaciclib plus fulvestrant improved median PFS vs.placebo(11.41 months vs.5.59 months,HR:0.480;95%CI:0.322-0.715).Abemaciclib numerically improved ORR.Although immature,a trend toward OS benefit with abemaciclib was observed(cohort A:HR:0.893,95%CI:0.553-1.443;cohort B:HR:0.512,95%CI:0.281-0.931).The most frequent grade≥3 adverse events in the abemaciclib arms were neutropenia,leukopenia,anemia(both cohorts),and lymphocytopenia(cohort B).Abemaciclib did not cause clinically meaningful changes in patient-reported global health,functioning,or most symptoms vs.placebo.Conclusions:Abemaciclib plus ET led to improvements in PFS and ORR,a manageable safety profile,and sustained HRQoL,providing clinical benefit without a high toxicity burden or reduced quality of life.
文摘目的:研究阿贝西利致不良反应的发生规律和特点,为临床安全合理用药提供参考。方法:检索中国知网、万方数据、维普网、PubMed、Web of Science等数据库自建库以来至2024年7月关于阿贝西利发生不良反应的个案报道,并进行统计分析。结果:共纳入文献34篇,涉及患者35例,其中包括女性31例(88.57%)和男性4例(11.43%),且以60岁以上的患者居多(18例,51.43%)。所患疾病多为乳腺癌(30例,85.71%)。发生不良反应时间为服药后4 d~23个月,主要集中在开始服药6个月内(25例,71.43%),主要累及消化系统、血液系统、呼吸系统、内分泌系统、心血管系统、免疫系统等。其中23例(65.71%)患者采取对症治疗后不良反应症状改善,2例(5.71%)患者因肺损伤治疗无效死亡。可见,阿贝西利存在潜在致死风险。结论:医务工作者应加强对阿贝西利不良反应的防范与监测,确保患者用药安全有效。
