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

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<0.05)。3个剂量组清除率分别为(7.02±2.46)、(5.80±1.25)、(3.66±1.32)L/h,差异具有统计学意义(F=6.02,P=0.009);与30 mg组比较,50 mg组清除率下降(P<0.05)。3个剂量组达峰浓度分别为(540.45±32.25)、(820.75±46.47)、(1014.78±64.96)mg/L,差异具有统计学意义(F=207.70,P<0.001);与30、40 mg组比较,50 mg组的达峰浓度增加(均P<0.05);与30 mg组比较,40 mg组达峰浓度增加(P<0.05)。动态监测4个治疗周期鞘内注射化疗后脑脊液药物浓度,其中30 mg组脑脊液浓度分别为(13.76±4.79)、(11.41±7.08)、(9.41±2.59)、(7.86±4.02)mg/L,40 mg组脑脊液浓度分别为(14.45±6.59)、(12.87±15.73)、(11.24±2.48)、(9.09±3.38)mg/L,50 mg组脑脊液浓度分别为(12.94±10.34)、(9.72±7.62)、(8.15±8.17)、(4.34±4.21)mg/L;30 mg组不同鞘内注射周期脑脊液中药物浓度差异有统计学意义(F=4.04,P=0.016),与第1周期相比,第3、4周期脑脊液中药物浓度下降(均P<0.05);40和50 mg组不同治疗周期脑脊液药物浓度差异均无统计学意义(F=0.28,P=0.837;F=3.57,P=0.066)。结论反相高效液相色谱法可有效检测脑脊液中培美曲塞浓度,动态监测脑脊液中培美曲塞浓度可以为肺腺癌LM患者临床鞘内注射化疗给药剂量和治疗周期提供依据。

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 mg groups were(5696.12±283.32),(7886.29±396.57),and(14202.70±440.19)h·mg/L,respectively,with a statistically significant difference(F=1159.00,P<0.001);AUC_(0-∞)increased in the 50 mg group compared to the 30 and 40 mg groups(both P<0.05);AUC_(0-∞)increased in the 40 mg group compared to the 30 mg group(P<0.05).The half-lives of three groups were(8.75±0.23),(11.29±0.59)and(16.42±1.23)h,respectively,with a statistically significant difference(F=206.80,P<0.001);half-life was longer in the 50 mg group compared to the 30 and 40 mg groups(both P<0.05);half-life was longer in the 40 mg group compared to the 30 mg group(P<0.05).The peak time of three groups were(1.55±0.10),(1.00±0.01),(1.43±0.11)h,respectively,with a statistically significant difference(F=48.11,P<0.001);the peak time was shorter in the 40 and 50 mg groups compared to the 30 mg group(both P<0.05).Clearance of three groups were(7.02±2.46),(5.80±1.25)and(3.66±1.32)L/h,respectively,with a statistically significant difference(F=6.02,P=0.009);clearance was decreased in the 50 mg group compared to the 30 mg group(P<0.05).The peak concentration of three groups were(540.45±32.25),(820.75±46.47)and(1014.78±64.96)mg/L,respectively,with a statistically significant difference(F=207.70,P<0.001);peak concentration increased in the 50 mg group compared to the 30 and 40 mg groups(both P<0.05);peak concentration increased in the 40 mg group compared to the 30 mg group(P<0.05).Cerebrospinal fluid drug concentrations were dynamically monitored after 4 cycles of intrathecal injection chemotherapy,in which cerebrospinal fluid pemetrexed concentrations in 30 mg group were(13.76±4.79),(11.41±7.08),(9.41±2.59)and(7.86±4.02)mg/L,respectively;40 mg group were(14.45±6.59),(12.87±15.73),(11.24±2.48)and(9.09±3.38)mg/L,respectively;50 mg group were(12.94±10.34),(9.72±7.62),(8.15±8.17)and(4.34±4.21)mg/L,respectively.There was a statistically significant difference in cerebrospinal fluid drug concentrations among different intrathecal injection chemotherapy cycles in 30 mg group(F=4.04,P=0.016),and the cerebrospinal fluid drug concentration decreased in cycles 3 and 4 compared to cycle 1(both P<0.05).There were no statistically significant differences in cerebrospinal fluid drug concentrations among different treatment cycles in 40 and 50 mg groups(F=0.28,P=0.837;F=3.57,P=0.066).Conclusion Reversed phase high performance liquid chromatography method can effectively detect the pemetrexed concentration in cerebrospinal fluid;dynamic monitoring of cerebrospinal fluid pemetrexed concentration can provide a basis for the dosage and the treatment cycle of intrathecal injection chemotherapy in LM patients with lung adenocarcinoma.