Mikkelsen Mette Schou, Blaakaer Jan, Petersen Lone Kjeld, Schleiss Luise Gram, Iversen Lene Hjerrild
Department of Gynecology and Obstetrics, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Pleura Peritoneum. 2020 Sep 7;5(4):20200137. doi: 10.1515/pp-2020-0137. eCollection 2020 Nov.
Carboplatin is frequently used in various doses for hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of epithelial ovarian cancer (EOC) although its pharmacokinetics, including focus on the perfusion time, has not been evaluated when used in modern era cytoreductive surgery (CRS). The aim was to evaluate the pharmacokinetics and hematological toxicity of carboplatin used for HIPEC with a perfusion time of 90 min.
Fifteen patients with stage III-IV primary EOC received CRS and 90 min of HIPEC with carboplatin at dose 800 mg/m. For the pharmacokinetic analysis, perfusate and blood samples were obtained during HIPEC and up to 48 h after HIPEC (blood only). Hematological toxicity within 30 days was graded according to Common Terminology Criteria for Adverse Events. Severe toxicity (grades 3-5) is reported.
Mean maximum concentration of carboplatin was 12 times higher in perfusate than plasma (mean CmaxPF=348 µg/mL (range: 279-595 µg/mL) versus mean CmaxPL=29 µg/mL (range: 21-39 µg/mL)). Mean terminal half-life of carboplatin in perfusate was 104 min (range: 63-190 min) and mean intraperitoneal-to-plasma area under the concentration-time curve (AUC) ratio was 12.3 (range: 7.4-17.2). Two patients (13%) had grade 3 neutropenia within 30 days. No grade 4-5 hematological toxicities were identified.
Carboplatin has a favorable pharmacokinetic profile for 90 min HIPEC administration, and the hematological toxicity was acceptable at dose 800 mg/m. Large interindividual differences were found in the pharmacokinetic parameters, making risk of systemic exposure difficult to predict.
尽管在现代肿瘤细胞减灭术（CRS）中使用卡铂进行热灌注化疗（HIPEC）治疗上皮性卵巢癌（EOC）时，其药代动力学（包括对灌注时间的关注）尚未得到评估，但卡铂仍经常以各种剂量用于该治疗。本研究旨在评估灌注时间为90分钟的卡铂用于HIPEC时的药代动力学和血液学毒性。
15例III-IV期原发性EOC患者接受了CRS以及90分钟的卡铂HIPEC治疗，卡铂剂量为800mg/m²。进行药代动力学分析时，在HIPEC期间及HIPEC后长达48小时（仅血液）采集灌注液和血液样本。根据不良事件通用术语标准对30天内的血液学毒性进行分级。报告严重毒性（3-5级）。
卡铂在灌注液中的平均最大浓度比血浆高12倍（平均CmaxPF = 348μg/mL（范围：279-595μg/mL），而平均CmaxPL = 29μg/mL（范围：21-39μg/mL））。卡铂在灌注液中的平均终末半衰期为104分钟（范围：63-190分钟），浓度-时间曲线下平均腹腔内与血浆面积比（AUC）为12.3（范围：7.4-17.2）。两名患者（13%）在30天内出现3级中性粒细胞减少。未发现4-5级血液学毒性。
卡铂在90分钟HIPEC给药时具有良好的药代动力学特征，且在800mg/m²剂量下血液学毒性可接受。药代动力学参数存在较大个体差异，使得全身暴露风险难以预测。
