Population pharmacokinetics of intraperitoneal irinotecan and SN-38 in patients with peritoneal metastases from colorectal origin.

Autor: Rietveld PCS; Department of Clinical Pharmacy, Erasmus MC, Rotterdam, The Netherlands.; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.; Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands., Sassen SDT; Department of Clinical Pharmacy, Erasmus MC, Rotterdam, The Netherlands.; Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands., Guchelaar NAD; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., van Eerden RAG; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., de Boer NL; Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., van den Heuvel TBM; Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands., Burger JWA; Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands., Mathijssen RHJ; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Koch BCP; Department of Clinical Pharmacy, Erasmus MC, Rotterdam, The Netherlands.; Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands., Koolen SLW; Department of Clinical Pharmacy, Erasmus MC, Rotterdam, The Netherlands.; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2024 Jun; Vol. 13 (6), pp. 1006-1016. Date of Electronic Publication: 2024 Apr 17.
DOI: 10.1002/psp4.13136
Abstrakt: 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.
(© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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