在CRC-PIPAC试验中，奥沙利铂经静电加压腹腔内气溶胶化疗（ePIPAC）腹腔给药后在不可切除的结直肠癌腹膜转移患者中的全身药代动力学。
Systemic Pharmacokinetics of Oxaliplatin After Intraperitoneal Administration by Electrostatic Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC) in Patients with Unresectable Colorectal Peritoneal Metastases in the CRC-PIPAC Trial.
作者信息
Lurvink Robin J, Tajzai Rudaba, Rovers Koen P, Wassenaar Emma C E, Moes Dirk-Jan A R, Pluimakers Giulia, Boerma Djamila, Burger Jacobus W A, Nienhuijs Simon W, de Hingh Ignace H J T, Deenen Maarten J
机构信息
Department of Surgery, Catharina Hospital, Michelangelolaan 2, 5623 EJ, Eindhoven, The Netherlands.
Department of Clinical Pharmacy, Catharina Hospital Eindhoven, Michelangelolaan 2, 5623 EJ, Eindhoven, The Netherlands.
出版信息
Ann Surg Oncol. 2021 Jan;28(1):265-272. doi: 10.1245/s10434-020-08743-9. Epub 2020 Jun 22.
BACKGROUND
Electrostatic pressurized intraperitoneal aerosol chemotherapy (ePIPAC) is a palliative treatment for unresectable peritoneal metastases from various primary cancers. However, little is known about the systemic pharmacokinetics of oxaliplatin after ePIPAC.
METHODS
Twenty patients with unresectable colorectal peritoneal metastases were treated with repetitive ePIPAC monotherapy with oxaliplatin (92 mg/m) and a simultaneous intravenous bolus of leucovorin (20 mg/m) and 5-fluorouracil (400 mg/m). Samples were collected during each ePIPAC: whole blood at t = 0, t = 5, t = 10, t = 20, t = 30, t = 60, t = 120, t = 240, t = 360 and t = 1080 min for plasma and plasma ultrafiltrate concentrations; urine at t = 0, t = 1, t = 3, t = 5 and t = 7 days. Samples were analyzed using atomic absorption spectrometry. Pharmacokinetics were analyzed using nonlinear mixed-effects modeling.
RESULTS
Four patients received one ePIPAC, three patients received two ePIPAC, and thirteen patients received ≥ 3 ePIPAC. The population pharmacokinetic models adequately described the pharmacokinetics of oxaliplatin after ePIPAC. The plasma ultrafiltrate C of oxaliplatin reached 1.36-1.90 µg/mL after 30 min with an AUC of 9.6-11.7 µg/mL * h. The plasma C reached 2.67-3.28 µg/mL after 90 min with an AUC of 49.0-59.5 µg/mL * h. The absorption rate constant (Ka) was 1.13/h. Urine concentrations of oxaliplatin rapidly decreased to less than 3.60 µg/mL in 90% of the samples at day 7.
DISCUSSION
Systemic exposure to oxaliplatin after ePIPAC seemed comparable to that after systemic chemotherapy, as described in other literature. Since this is an indirect comparison, future research should focus on the direct comparison between the systemic exposure to oxaliplatin after ePIPAC and after systemic chemotherapy.
TRIAL REGISTRATION
NCT03246321, Pre-results; ISRCTN89947480, Pre-results; NTR6603, Pre-results; EudraCT: 2017-000927-29, Pre-results.
背景
静电加压腹腔内气溶胶化疗（ePIPAC）是一种针对各种原发性癌症不可切除腹膜转移的姑息性治疗方法。然而，关于ePIPAC后奥沙利铂的全身药代动力学知之甚少。
方法
20例不可切除的结直肠腹膜转移患者接受了重复的ePIPAC单药治疗，使用奥沙利铂（92mg/m），同时静脉推注亚叶酸钙（20mg/m）和5-氟尿嘧啶（400mg/m）。在每次ePIPAC期间采集样本：在t = 0、t = 5、t = 10、t = 20、t = 30、t = 60、t = 120、t = 240、t = 360和t = 1080分钟采集全血用于血浆和血浆超滤液浓度检测；在t = 0、t = 1、t = 3、t = 5和t = 7天采集尿液。使用原子吸收光谱法分析样本。使用非线性混合效应模型分析药代动力学。
结果
4例患者接受了1次ePIPAC，3例患者接受了2次ePIPAC，13例患者接受了≥3次ePIPAC。群体药代动力学模型充分描述了ePIPAC后奥沙利铂的药代动力学。奥沙利铂的血浆超滤液C在30分钟后达到1.36 - 1.90μg/mL，AUC为9.6 - 11.7μg/mL*h。血浆C在90分钟后达到2.67 - 3.28μg/mL，AUC为
49.0 - 59.5μg/mL*h。吸收速率常数（Ka）为1.13/h。在第7天，90%的样本中奥沙利铂的尿液浓度迅速降至低于3.60μg/mL。
讨论
如其他文献所述，ePIPAC后奥沙利铂的全身暴露似乎与全身化疗后的暴露相当。由于这是间接比较，未来的研究应集中在ePIPAC后和全身化疗后奥沙利铂全身暴露的直接比较上。
试验注册
NCT03246321，结果未公布；ISRCTN89947480，结果未公布；NTR6603，结果未公布；EudraCT：2017 - 000927 - 29，结果未公布。
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