Abstract:

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 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. 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 （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 （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 （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 （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.

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