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Abstract 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.

The number of pharmacokinetic (PK) models of meropenem is increasing. However, the daily role of these PK models in the clinic remains unclear, especially for critically ill patients. Therefore, we evaluated the published meropenem models on real-world ICU data to assess their suitability for use in clinical practice. All models were built in NONMEM and evaluated using prediction and simulation-based diagnostics for the ability to predict the subsequent meropenem concentrations without plasma concentrations (a priori), and with plasma concentrations (a posteriori), for use in therapeutic drug monitoring (TDM). Eighteen PopPK models were included for evaluation. The a priori fit of the models, without the use of plasma concentrations, was poor, with a prediction error (PE)% of the interquartile range (IQR) exceeding the ±30% threshold. The fit improved when one to three concentrations were used to improve model predictions for TDM purposes. Two models were in the acceptable range with an IQR PE% within ±30%, when two or three concentrations were used. The role of PK models to determine the starting dose of meropenem in this population seems limited. However, certain models might be suitable for TDM-based dose adjustment using two to three plasma concentrations.

Haloperidol is considered the first-line treatment for delirium in critically ill patients. However, clinical evidence of efficacy is lacking and no pharmacokinetic studies have been performed in intensive care unit (ICU) patients. The aim of this study was to establish a pharmacokinetic model to describe the PK in this population to improve insight into dosing. One hundred and thirty-nine samples from 22 patients were collected in a single-center study in adults with ICU delirium who were treated with low-dose intravenous haloperidol (3–6 mg per day). We conducted a population pharmacokinetic analysis using Nonlinear Mixed Effects Modelling (NONMEM). A one-compartment model best described the data. The mean population estimates were 51.7 L/h (IIV 42.1%) for clearance and 1490 L for the volume of distribution. The calculated half-life was around 22 h (12.3–29.73 h) for an average patient. A negative correlation between C-Reactive Protein (CRP) and haloperidol clearance was observed, where clearance decreased significantly with increasing CRP up to a CRP concentration of 100 mg/L. This is the first step towards haloperidol precision dosing in ICU patients and our results indicate a possible role of inflammation.