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

国际肿瘤学杂志››2023,Vol. 50››Issue (10): 585-591.doi:10.3760/cma.j.cn371439-20230612-00112

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

谢宇, 郑胜男, 黄明敏, 郭爱斌, 尹震宇, 林永娟()

南京大学医学院附属鼓楼医院老年肿瘤科，南京 210008

收稿日期:2023-06-12修回日期:2023-09-12出版日期:2023-10-08发布日期:2023-11-08
通讯作者:林永娟 E-mail:lingyongjuan0218@126.com
作者简介:第一联系人：谢宇和郑胜男对本文有同等贡献
基金资助:
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);江苏省干部保健科研课题(BJ19001);希思科-豪森肿瘤研究基金(Y-HS2019-5)

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

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

Received:2023-06-12Revised:2023-09-12Online:2023-10-08Published:2023-11-08
Contact:Lin Yongjuan E-mail:lingyongjuan0218@126.com
About author:First author contact:Xie Yu and Zheng Shengnan are contributed equally to the article
Supported by:
Elderly Health Research Project of Jiangsu Province(LKZ2023013);Medical Key Science and Technology Development Project of Nanjing(ZKX18014);Cadre Health Care Project of Jiangsu Province(BJ18006);Cadre Health Care Project of Jiangsu Province(BJ19001);Cancer Research Funding of CSCO-Hausen(Y-HS2019-5)

摘要/Abstract

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（5 696.12±283.32）、（7 886.29±396.57）、（14 202.70±440.19）h·mg/L，差异具有统计学意义（F=1 159.00，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）、（1 014.78±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。

关键词:肺腺癌,脑膜癌病,注射，脊髓,培美曲塞,药代动力学

Abstract:

ObjectiveTo 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.MethodsA total of 21 patients with lung adenocarcinoma LM who underwent pemetrexed intrathecal injection chemotherapyviaOmmaya 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 drug-related 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.ResultsThere 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 （allP<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 （allP<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 （5 696.12±283.32），（7 886.29±396.57）， and （14 202.70±440.19） h·mg/L， respectively， with a statistically significant difference （F=1 159.00，P<0.001）； AUC_0-∞increased in the 50 mg group compared to the 30 and 40 mg groups （bothP<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 （bothP<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 （bothP<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 （1 014.78±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 （bothP<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 （bothP<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）.ConclusionReversed 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.

Key words:Adenocarcinoma of lung,Meningeal carcinomatosis,Injections， spinal,Pemetrexed,Pharmacokinetics

谢宇, 郑胜男, 黄明敏, 郭爱斌, 尹震宇, 林永娟. 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[J]. 国际肿瘤学杂志, 2023, 50(10): 585-591.

Xie Yu, Zheng Shengnan, Huang Mingmin, Guo Aibin, Yin Zhenyu, Lin Yongjuan. Pemetrexed clinical trial for intrathecal injection chemotherapy based on cerebrospinal fluid pharmacokinetics in patients with leptomeningeal metastasis from lung adenocarcinoma[J]. Journal of International Oncology, 2023, 50(10): 585-591.

图/表4

表1

21例接受培美曲塞鞘内注射化疗的肺腺癌LM患者临床特征（例/ $\bar{x} \pm s$）"

基本指标	30 mg组（n=10）	40 mg组（n=4）	50 mg组（n=7）	χ²/ F值	P值
性别
男	3	2	3	0.80	0.725
女	7	2	4	0.80	0.725
年龄（岁）
≤65	10	4	6	2.12	0.524
>65	0	0	1	2.12	0.524
吸烟史
既往或目前吸烟	4	2	3	0.34	>0.999
无吸烟史	6	2	4	0.34	>0.999
肺癌至LM时间（月）
≤24	6	3	3	1.15	0.622
>24	4	1	4	1.15	0.622
LM临床症状
头痛/恶心/呕吐	8	3	5	0.52	>0.999
肢体乏力麻木	2	0	2	1.17	0.789
颅神经障碍	5	2	4	0.31	>0.999
癫痫	1	0	1	0.83	>0.999
颈项强直	2	1	2	0.52	>0.999
合并脑转移
是	5	3	4	0.79	0.850
否	5	1	3	0.79	0.850
KPS评分（分）	61.00±14.49	60.00±14.14	65.71±11.34	0.33	0.723
头痛评分（分）	3.60±1.58	4.00±2.45	4.29±4.03	0.13	0.879
RANO评分（分）
≤4	4	1	4	1.15	0.622
>4	6	3	3	1.15	0.622
脑脊液细胞学阳性
是	8	3	6	0.59	>0.999
否	2	1	1	0.59	>0.999
典型磁共振异常
有	8	3	5	0.52	>0.999
无	2	1	2	0.52	>0.999
基因型
EGFR突变	9	3	6	1.05	0.763
ALK重排	1	1	1	1.05	0.763

表1

表2

21例接受不同剂量培美曲塞鞘内注射化疗的肺腺癌LM患者48 h内脑脊液中药物浓度分析（$\bar{x} \pm s$，mg/L）"

时间（h）	30 mg组（n=10）	40 mg组（n=4）	50 mg组（n=7）	F/t值	P值
0	11.52±12.56	24.06±9.77	22.44±16.69	1.87	0.184
0.5	277.96±92.34^a	267.99±50.69^a	-	0.20	0.844
1	593.29±305.68^a	631.61±191.06^a	986.20±256.81^ab	4.58	0.025
2	271.96±112.75^a	468.57±114.75^ab	436.11±137.68^ab	5.54	0.013
4	221.79±91.66^a	345.40±53.34^a	578.00±292.91^ab	7.88	0.003
6	176.04±91.89^a	225.66±111.91^a	311.34±56.46^ab	5.12	0.017
12	153.50±65.56^a	180.31±95.10^a	252.11±75.44^ab	3.66	0.046
24	133.93±90.99^a	55.17±31.72^b	275.03±17.95^abc	16.15	<0.001
48	14.69±10.40	14.85±10.18	19.22±10.23	0.44	0.650
F值	20.56	27.06	28.63
P值	<0.001	<0.001	<0.001

表2

表3

21例接受不同剂量培美曲塞鞘内注射化疗的肺腺癌LM患者脑脊液中药代动力学参数（$\bar{x} \pm s$）"

指标	30 mg组（n=10）	40 mg组（n=4）	50 mg组（n=7）	F值	P值
AUC_0-∞（h·mg/L）	5 696.12±283.32	7 886.29±396.57^a	14 202.70±440.19^ab	1 159.00	<0.001
MRT_0-∞（h）	13.14±3.20	13.20±8.21	14.31±3.82	0.15	0.865
Zeta（1/h）	0.085±0.023	0.073±0.030	0.060±0.029	1.86	0.185
半衰期（h）	8.75±0.23	11.29±0.59^a	16.42±1.23^ab	206.80	<0.001
达峰时间（h）	1.55±0.10	1.00±0.01^a	1.43±0.11^a	48.11	<0.001
表观分布容积（L）	78.00±4.82	76.67±5.78	73.72±2.48	1.98	0.168
清除率（L/h）	7.02±2.46	5.80±1.25	3.66±1.32^a	6.02	0.009
达峰浓度（mg/L）	540.45±32.25	820.75±46.47^a	1 014.78±64.96^ab	207.70	<0.001

表3

治疗周期（个）	30 mg组（n=10）	40 mg组（n=4）	50 mg组（n=7）
1	13.76±4.79	14.45±6.59	12.94±10.34
2	11.41±7.08	12.87±15.73	9.72±7.62
3	9.41±2.59^a	11.24±2.48	8.15±8.17
4	7.86±4.02^a	9.09±3.38	4.34±4.21
F值	4.04	0.28	3.57
P值	0.016	0.837	0.066

表4

参考文献21

[1]	Li N, Bian Z, Cong M, et al. Survival outcomes of patients with epidermal growth factor receptor mutations in non-small cell lung cancer with leptomeningeal metastasis[J].Front Oncol,2021,11: 723562. DOI:10.3389/fonc.2021.723562.
[2]	Fan C, Zhao Q, Li L, et al. Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating tyrosine kinase inhibitor-failed leptomeningeal metastases from EGFR-mutant NSCLC—a prospective, open-label, single-arm phase 1/2 clinical trial (unique identifier: ChiCTR1800016615)[J].J Thorac Oncol,2021,16(8): 1359-1368. DOI:10.1016/j.jtho.2021.04.018.
[3]	Zhou T, Zhu S, Xiong Q, et al. Intrathecal chemotherapy combined with systemic therapy in patients with refractory leptomeningeal metastasis of non-small cell lung cancer: a retrospective study[J].BMC Cancer,2023,23(1): 333. DOI:10.1186/s12885-023-10806-5. pmid:37041504
[4]	Wang Y, Yang X, Li NJ, et al. Leptomeningeal metastases in non-small cell lung cancer: diagnosis and treatment[J].Lung Cancer,2022,174: 1-13. DOI:10.1016/j.lungcan.2022.09.013. pmid:36206679
[5]	Li H, Zheng S, Lin Y, et al. Safety, pharmacokinetic and clinical activity of intrathecal chemotherapy with pemetrexed via the ommaya reservoir for leptomeningeal metastases from lung adenocarcinoma: a prospective phase Ⅰ study[J].Clin Lung Cancer,2023,24(2): e94-e104. DOI:10.1016/j.cllc.2022.11.011.
[6]	Le Rhun E, Weller M, Brandsma D, et al. EANO-ESMO clinical practice guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours[J].Ann Oncol,2017,28(suppl_4): iv84-iv99. DOI:10.1093/annonc/mdx221.
[7]	Cao Y, Na W, Su H, et al. Subarachnoid hemorrhage caused by spontaneous intracranial hypotension: two rare cases report[J].Int J Neurosci,2023,133(1): 51-54. DOI:10.1080/00207454.2021.1881094.
[8]	Volkov AA, Filis AK, Vrionis FD. Surgical treatment for leptome-ningeal disease[J].Cancer Control,2017,24(1): 47-53. DOI:10.1177/107327481702400107.
[9]	Kim HS, Park JB, Gwak HS, et al. Clinical outcome of cerebrospinal fluid shunts in patients with leptomeningeal carcinomatosis[J].World J Surg Oncol,2019,17(1): 59. DOI:10.1186/s12957-019-1595-7. pmid:30917830
[10]	Lin N, Dunn IF, Glantz M, et al. Benefit of ventriculoperitoneal cerebrospinal fluid shunting and intrathecal chemotherapy in neoplastic meningitis: a retrospective, case-controlled study[J].J Neurosurg,2011,115(4): 730-736. DOI:10.3171/2011.5.JNS101768. pmid:21721878
[11]	Dai H, Chen Y, Elmquist WF. Distribution of the novel antifolate pemetrexed to the brain[J].J Pharmacol Exp Ther,2005,315(1): 222-229. DOI:10.1124/jpet.105.090043. pmid:15987831
[12]	Stapleton SL, Reid JM, Thompson PA, et al. Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates[J].Cancer Chemother Pharmacol,2007,59(4): 461-466. DOI:10.1007/s00280-006-0285-7.
[13]	Sun JM, Nam MH, Chung JY, et al. Safety and pharmacokinetics of intrathecal administration of pemetrexed in rats[J].Cancer Chemother Pharmacol,2011,68(2): 531-538. DOI:10.1007/s00280-010-1522-7.
[14]	Paris J, Angeli E, Bousquet G. The pharmacology of xenobiotics after intracerebro spinal fluid administration: implications for the treatment of brain tumors[J].Int J Mol Sci,2021,22(3): 1281. DOI:10.3390/ijms22031281.
[15]	Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial[J].Lancet Oncol,2013, 14(3): 199-209. DOI:10.1016/S1470-2045(12)70600-9.
[16]	Fleischhack G, Jaehde U, Bode U. Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis[J].Clin Pharmacokinet,2005,44(1): 1-31. DOI:10.2165/00003088-200544010-00001. pmid:15634030
[17]	Palmisciano P, Watanabe G, Conching A, et al. Intrathecal therapy for the management of leptomeningeal metastatic disease: a scoping review of the current literature and ongoing clinical trials[J].J Neurooncol,2022,160(1): 79-100. DOI:10.1007/s11060-022-04118-0.
[18]	Triarico S, Maurizi P, Mastrangelo S, et al. Improving the brain delivery of chemotherapeutic drugs in childhood brain tumors[J].Cancers (Basel),2019,11(6):824. DOI:10.3390/cancers11060824.
[19]	Rollins NK. Using ADC to study the brain in early childhood: not for the uninitiated[J].Radiology,2021,298(2): 425-426. DOI:10.1148/radiol.2020204158. pmid:33290175
[20]	Pan Z, Yang G, Cui J, et al. A pilot phase 1 study of intrathecal pemetrexed for refractory leptomeningeal metastases from non-small-cell lung cancer[J].Front Oncol,2019,9: 838. DOI:10.3389/fonc.2019.00838. pmid:31544065
[21]	Pan Z, Yang G, He H, et al. Intrathecal pemetrexed combined with involved-field radiotherapy as a first-line intra-CSF therapy for leptomeningeal metastases from solid tumors: a phase Ⅰ/Ⅱ study[J].Ther Adv Med Oncol,2020,17(7): 12-17. DOI:10.1177/1758835920937953.