Role of Inflammation in Irinotecan (CPT‐11) Pharmacokinetics: A PK Study and Development of a Best‐fit Pharmacokinetic Model of Irinotecan and Its Active Metabolite, SN‐38 in Mice with and without Inflammation

Abstract

PurposeIrinotecan is a potent and widely used anticancer drug for the treatment of metastatic colorectal cancer and elevated concentrations of its active metabolite, SN‐38, causes severe diarrhea, which is a dose‐limiting toxicity of irinotecan. It has been previously reported that inflammation downregulates the expression and activity of UGT1A1 and carboxylesterase enzymes, which are involved in the metabolism of irinotecan to SN‐38. However, the role of inflammation in the metabolism and disposition of irinotecan has never been studied. Therefore, the aim of this study was to investigate whether the pharmacokinetics of Irinotecan is altered during inflammation and to develop a model to predict irinotecan and SN‐38 pharmacokinetics during inflammation.MethodsPharmacokinetic StudyMale C57BL6 mice of 5–6 weeks age were injected either saline or LPS (2 mg/kg) via I.P route and irinotecan (10 mg/kg) was administered via oral gavage after 1 or 16 h of LPS injection. After irinotecan was given, blood samples were collected from 0–24 h at different time points from the tail vein and the samples were analyzed for irinotecan, SN‐38, and SN‐38 glucuronide concentrations by LC‐MS/MS.Determination of Pharmacokinetic ParametersAUC, Cmax, and Tmax values for irinotecan, SN‐38, and SN‐38G were calculated using Phoenix WinNonlin 5.2 software.Pharmacokinetic ModelingA pharmacokinetic model was developed using Phoenix® NLME™ software to simultaneously predict irinotecan and SN‐38 concentrations during inflammation. A correlation between the observed and predicted concentrations of Irinotecan and SN‐38 pharmacokinetic data was obtained by individual fitting for each mouse in saline and LPS‐treated mouse groups.ResultsThe blood concentrations of both irinotecan and SN‐38 were significantly higher in mice treated with LPS as compared to saline treated mice. A second peak in the pharmacokinetic profile of SN‐38 was observed that correlated to enterohepatic recycling. The AUC and Cmax values of irinotecan were 3 and 2.5‐fold higher in LPS treated mice. Similarly, the AUC and Cmax values of SN‐38 were approximately 2 and 2.5‐fold higher in LPS‐treated mice compared with saline‐treated mice. However, there were no significant changes observed in the AUC and Cmax values of SN‐38G between control and LPS‐treated mice. The diagnostic plots for the pharmacokinetic model of individual PK show that there is a good correlation between individual predicted concentration vs time and observed concentration vs predicted concentration.ConclusionOur study shows an important finding that the blood concentrations of the toxic SN‐38 metabolite were significantly elevated in mice with inflammation. Moreover, the AUC of SN‐38 was 2‐fold higher in LPS‐treated mice. These results indicate that patients with inflammation may have a very high risk of experiencing gastrointestinal toxicity upon irinotecan administration due to increased SN‐38 concentrations. Additionally, a pharmacokinetic model was developed, and a good correlation was obtained to predict irinotecan and SN‐38 concentrations during inflammation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.