基于脑脊液药代动力学的培美曲塞应用于肺腺癌软脑膜转移患者鞘内注射化疗的临床研究  

Pemetrexed clinical trial for intrathecal injection chemotherapy based on cerebrospinal fluidpharmacokinetics in patients with leptomeningeal metastasis from lung adenocarcinoma

作　　者：谢宇[1] 郑胜男 黄明敏[1] 郭爱斌[1] 尹震宇[1] 林永娟[1] Xie Yu;Zheng Shengnan;Huang Mingmin;Guo Aibin;Yin Zhenyu;Lin Yongjuan(Department of Geriatric Oncology,Nanjing Drum Tower Hospital,Affiliated Hospital of Nanjing University Medical School,Nanjing 210008,China)

机构地区：[1]南京大学医学院附属鼓楼医院老年肿瘤科,南京210008

出　　处：《国际肿瘤学杂志》2023年第10期585-591,共7页Journal of International Oncology

基　　金：江苏省老年健康科研项目(LKZ2023013);南京市医学重点科技发展项目(ZKX18014);江苏省干部保健科研课题(BJ18006、BJ19001);希思科-豪森肿瘤研究基金(Y-HS2019-5)。

摘　　要：目的研究肺腺癌软脑膜转移(LM)患者鞘内注射化疗后脑脊液培美曲塞的药代动力学,以指导临床鞘内注射化疗的给药方案。方法收集2019年11月至2022年11月于南京大学医学院附属鼓楼医院经Ommaya囊行培美曲塞鞘内注射化疗的肺腺癌LM患者共21例,根据培美曲塞剂量分为30、40、50 mg组(n=10、n=4、n=7),各组于首次鞘内注射后0、0.5、1、2、4、6、12、24、48 h留取脑脊液,每个治疗周期第8天留取脑脊液。采用反相高效液相色谱法测定脑脊液中药物浓度,明确药物相关药代动力学参数,比较各剂量组间脑脊液中培美曲塞浓度差异;观察并比较不同治疗周期鞘内注射化疗后脑脊液培美曲塞浓度变化。结果不同剂量组患者首次鞘内注射后0、0.5、1、2、4、6、12、24、48 h脑脊液中药物浓度差异均具有统计学意义(30 mg组:F=20.56,P<0.001;40 mg组:F=27.06,P<0.001;50 mg组:F=28.63,P<0.001),鞘内注射后0.5、1、2、4、6、12 h与鞘内注射0 h相比,各剂量组脑脊液药物浓度差异均有统计学意义(均P<0.05)。相较于30 mg组,50 mg组鞘内注射后1、2、4、6、12、24 h脑脊液中药物浓度增加,差异均具有统计学意义(均P<0.05)。脑脊液培美曲塞药代动力学分析显示,30、40和50 mg组药物浓度-时间曲线下面积(AUC)_(0-∞)分别为(5696.12±283.32)、(7886.29±396.57)、(14202.70±440.19)h·mg/L,差异具有统计学意义(F=1159.00,P<0.001);与30、40 mg组比较,50 mg组AUC_(0-∞)增加(均P<0.05);与30 mg组比较,40 mg组AUC_(0-∞)增加(P<0.05)。3个剂量组半衰期分别为(8.75±0.23)、(11.29±0.59)、(16.42±1.23)h,差异具有统计学意义(F=206.80,P<0.001);与30、40 mg组比较,50 mg组半衰期延长(均P<0.05);与30 mg组比较,40 mg组半衰期延长(P<0.05)。3个剂量组达峰时间分别为(1.55±0.10)、(1.00±0.01)、(1.43±0.11)h,差异具有统计学意义(F=48.11,P<0.001);与30 mg组比较,40、50 mg组脑脊液中药物浓度达峰时间变短(均P<0.Objective To investigate the pharmacokinetics of cerebrospinal fluid pemetrexed following intrathecal injection chemotherapy in patients with leptomeningeal metastasis(LM)from lung adenocarcinoma and provide a basis for clinical intrathecal injection chemotherapy.Methods A total of 21 patients with lung adenocarcinoma LM who underwent pemetrexed intrathecal injection chemotherapy via Ommaya capsule at Nanjing Drum Tower Hospital,Aiffilitated Hospital of Nanjing University Medical School from November 2019 to November 2022 were collected,and divided into 30,40 and 50 mg groups(n=10,n=4,n=7)according to pemetrexed dose.Cerebrospinal fluid was collected at 0,0.5,1,2,4,6,12,24 and 48 h after the first intrathecal injection chemotherapy,and day 8 of each cycle for three groups.Reversed phase high performance liquid chromatography was used to determine the drug concentration in cerebrospinal fluid,to clarify the drugrelated pharmacokinetic parameters,and to compare the differences in pemetrexed concentration among groups.Finally,cerebrospinal fluid pemetrexed concentration changes were observed and compared after different intrathecal injection chemotherapy cycles.Results There were statistically significant differences in cerebrospinal fluid drug concentrations of patients in three groups at 0,0.5,1,2,4,6,12,24 and 48 h after the first intrathecal injection chemotherapy(30 mg group:F=20.56,P<0.001;40 mg group:F=27.06,P<0.001;50 mg group:F=28.63,P<0.001),and there were statistically significant differences in the concentration of cerebrospinal fluid drugs in each dose group at 0.5,1,2,4,6 and 12 h compared to 0 h after intrathecal injection chemotherapy(all P<0.05).Compared to the 30 mg group,cerebrospinal fluid drug concentrations in the 50 mg group increased at 1,2,4,6,12 and 24 h after intrathecal injection chemotherapy,with statistically significant differences(all P<0.05).Pharmacokinetic analysis of cerebrospinal fluid pemetrexed showed that area under the concentration-time curve(AUC)_(0-∞)of the 30,40 and 50 m

关 键 词：肺腺癌 脑膜癌病 注射 脊髓 培美曲塞 药代动力学 

分 类 号：R734.2[医药卫生—肿瘤]