Pascale C. S. Rietveld, Sebastiaan D. T. Sassen, Niels A. D. Guchelaar, Ruben A. G. van Eerden, Nadine L. de Boer, Teun B. M. van den Heuvel, Jacobus W. A. Burger, Ron H. J. Mathijssen, Birgit C. P. Koch, Stijn L. W. Koolen
{"title":"大肠癌腹膜转移患者腹腔注射伊立替康和 SN-38 的群体药代动力学。","authors":"Pascale C. S. Rietveld, Sebastiaan D. T. Sassen, Niels A. D. Guchelaar, Ruben A. G. van Eerden, Nadine L. de Boer, Teun B. M. van den Heuvel, Jacobus W. A. Burger, Ron H. J. Mathijssen, Birgit C. P. Koch, Stijn L. W. Koolen","doi":"10.1002/psp4.13136","DOIUrl":null,"url":null,"abstract":"<p>Peritoneal metastases (PM) are common in patients with colorectal cancer. Patients with PM have a poor prognosis, and for those who are not eligible for cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), palliative chemotherapy is currently the only option. Recently, we conducted a phase I trial (INTERACT) in which irinotecan was administered intraperitoneally (IP) to 18 patients ineligible for CRS-HIPEC. The primary objective was to evaluate covariates influencing the PK profile of irinotecan and SN-38 after IP administration. Secondly, a population PK model was developed to support the further development of IP irinotecan by improving dosing in patients with PM. Patients were treated with IP irinotecan every 2 weeks in combination with systemic FOLFOX-bevacizumab. Irinotecan and SN-38 were measured in plasma (588 samples) and SN-38 was measured in peritoneal fluid (267 samples). Concentration-Time data were log-transformed and analyzed using NONMEM version 7.5 using FOCE+I estimation. An additive error model described the residual error, with inter-individual variability in PK parameters modeled exponentially. The final structural model consisted of five compartments. Weight was identified as a covariate influencing the SN-38 plasma volume of distribution and GGT was found to influence the SN-38 plasma clearance. This population PK model adequately described the irinotecan and SN-38 in plasma after IP administration, with weight and GGT as predictive factors. Irinotecan is converted intraperitoneal to SN-38 by carboxylesterases and the plasma bioavailability of irinotecan is low. This model will be used for the further clinical development of IP irinotecan by providing dosing strategies.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.13136","citationCount":"0","resultStr":"{\"title\":\"Population pharmacokinetics of intraperitoneal irinotecan and SN-38 in patients with peritoneal metastases from colorectal origin\",\"authors\":\"Pascale C. S. Rietveld, Sebastiaan D. T. Sassen, Niels A. D. Guchelaar, Ruben A. G. van Eerden, Nadine L. de Boer, Teun B. M. van den Heuvel, Jacobus W. A. Burger, Ron H. J. Mathijssen, Birgit C. P. Koch, Stijn L. W. Koolen\",\"doi\":\"10.1002/psp4.13136\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Peritoneal metastases (PM) are common in patients with colorectal cancer. Patients with PM have a poor prognosis, and for those who are not eligible for cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), palliative chemotherapy is currently the only option. Recently, we conducted a phase I trial (INTERACT) in which irinotecan was administered intraperitoneally (IP) to 18 patients ineligible for CRS-HIPEC. The primary objective was to evaluate covariates influencing the PK profile of irinotecan and SN-38 after IP administration. Secondly, a population PK model was developed to support the further development of IP irinotecan by improving dosing in patients with PM. Patients were treated with IP irinotecan every 2 weeks in combination with systemic FOLFOX-bevacizumab. Irinotecan and SN-38 were measured in plasma (588 samples) and SN-38 was measured in peritoneal fluid (267 samples). Concentration-Time data were log-transformed and analyzed using NONMEM version 7.5 using FOCE+I estimation. An additive error model described the residual error, with inter-individual variability in PK parameters modeled exponentially. The final structural model consisted of five compartments. Weight was identified as a covariate influencing the SN-38 plasma volume of distribution and GGT was found to influence the SN-38 plasma clearance. This population PK model adequately described the irinotecan and SN-38 in plasma after IP administration, with weight and GGT as predictive factors. Irinotecan is converted intraperitoneal to SN-38 by carboxylesterases and the plasma bioavailability of irinotecan is low. This model will be used for the further clinical development of IP irinotecan by providing dosing strategies.</p>\",\"PeriodicalId\":10774,\"journal\":{\"name\":\"CPT: Pharmacometrics & Systems Pharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-04-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.13136\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CPT: Pharmacometrics & Systems Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/psp4.13136\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"CPT: Pharmacometrics & Systems Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/psp4.13136","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
摘要
腹膜转移(PM)在结直肠癌患者中很常见。腹膜转移瘤患者的预后较差,对于那些不符合接受囊肿切除手术(CRS)联合或不联合腹腔热化疗(HIPEC)的患者,姑息化疗是目前唯一的选择。最近,我们开展了一项 I 期试验(INTERACT),对 18 名不符合 CRS-HIPEC 条件的患者腹腔注射伊立替康(IP)。主要目的是评估 IP 给药后影响伊立替康和 SN-38 PK 谱的协变量。其次,通过改进PM患者的用药剂量,建立一个群体PK模型,以支持IP伊立替康的进一步开发。患者每 2 周接受一次 IP 伊立替康治疗,并同时接受 FOLFOX-bevacizumab 全身治疗。在血浆(588 个样本)中测定了伊立替康和 SN-38,在腹腔液(267 个样本)中测定了 SN-38。浓度-时间数据经对数变换后使用 NONMEM 7.5 版进行分析,并使用 FOCE+I 估算。一个加性误差模型描述了残余误差,PK 参数的个体间变异性以指数方式建模。最终的结构模型由五个部分组成。体重被确定为影响 SN-38 血浆分布容积的协变量,GGT 被发现影响 SN-38 血浆清除率。该群体 PK 模型充分描述了 IP 给药后血浆中伊立替康和 SN-38的情况,体重和 GGT 是预测因素。伊立替康在腹腔内会被羧基酯酶转化为 SN-38,因此伊立替康的血浆生物利用度较低。该模型将为 IP 伊立替康的进一步临床开发提供剂量策略。
Population pharmacokinetics of intraperitoneal irinotecan and SN-38 in patients with peritoneal metastases from colorectal origin
Peritoneal metastases (PM) are common in patients with colorectal cancer. Patients with PM have a poor prognosis, and for those who are not eligible for cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), palliative chemotherapy is currently the only option. Recently, we conducted a phase I trial (INTERACT) in which irinotecan was administered intraperitoneally (IP) to 18 patients ineligible for CRS-HIPEC. The primary objective was to evaluate covariates influencing the PK profile of irinotecan and SN-38 after IP administration. Secondly, a population PK model was developed to support the further development of IP irinotecan by improving dosing in patients with PM. Patients were treated with IP irinotecan every 2 weeks in combination with systemic FOLFOX-bevacizumab. Irinotecan and SN-38 were measured in plasma (588 samples) and SN-38 was measured in peritoneal fluid (267 samples). Concentration-Time data were log-transformed and analyzed using NONMEM version 7.5 using FOCE+I estimation. An additive error model described the residual error, with inter-individual variability in PK parameters modeled exponentially. The final structural model consisted of five compartments. Weight was identified as a covariate influencing the SN-38 plasma volume of distribution and GGT was found to influence the SN-38 plasma clearance. This population PK model adequately described the irinotecan and SN-38 in plasma after IP administration, with weight and GGT as predictive factors. Irinotecan is converted intraperitoneal to SN-38 by carboxylesterases and the plasma bioavailability of irinotecan is low. This model will be used for the further clinical development of IP irinotecan by providing dosing strategies.