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Background: Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients. Objectives: To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function. Methods: A population pharmacokinetic model was developed in NONMEM (R) 7.3 based on steady-state meropenem concentrations (C-ss) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRcG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90% of the patients. Probability of target attainment was determined for efficacy (C-ss >= 8 mg/L) and potentially increased likelihood of adverse drug reactions (C-ss >32 mg/L). Results: In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P-0.05 - P-0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/ 3940 mg were required to reach a target C-ss = 8 mg/L in 90% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions (<0.5%) was associated with these doses. Conclusions: A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population.
Context Optimization of hydrocortisone replacement therapy is important to prevent under- and over dosing. Hydrocortisone pharmacokinetics is complex as circulating cortisol is protein bound mainly to corticosteroid-binding globulin (CBG) that has a circadian rhythm. Objective A detailed analysis of the CBG circadian rhythm and its impact on cortisol exposure after hydrocortisone administration. Design and Methods CBG was measured over 24 hours in 14 healthy individuals and, employing a modelling and simulation approach using a semi-mechanistic hydrocortisone pharmacokinetic model, we evaluated the impact on cortisol exposure (area under concentration-time curve and maximum concentration of total cortisol) of hydrocortisone administration at different clock times and of the changing CBG concentrations. Results The circadian rhythm of CBG was well described with two cosine terms added to the baseline of CBG: baseline CBG was 21.8 mu g/mL and interindividual variability 11.9%; the amplitude for the 24 and 12 hours cosine functions were relatively small (24 hours: 5.53%, 12 hours: 2.87%) and highest and lowest CBG were measured at 18:00 and 02:00, respectively. In simulations, the lowest cortisol exposure was observed after administration of hydrocortisone at 23:00-02:00, whereas the highest was observed at 15:00-18:00. The differences between the highest and lowest exposure were minor (<= 12.2%), also regarding the free cortisol concentration and free fraction (<= 11.7%). Conclusions Corticosteroid-binding globulin has a circadian rhythm but the difference in cortisol exposure is <= 12.2% between times of highest and lowest CBG concentrations; therefore, hydrocortisone dose adjustment based on time of dosing to adjust for the CBG concentrations is unlikely to be of clinical benefit.
Background:
Hemadsorption of cytokines is used in critically ill patients with sepsis or septic shock. Concerns have been raised that the cytokine adsorber CytoSorb (R) unintentionally adsorbs vancomycin. This study aimed to quantify vancomycin elimination by CytoSorb (R) .
Methods:
Critically ill patients with sepsis or septic shock receiving continuous renal replacement therapy and CytoSorb (R) treatment during a prospective observational study were included in the analysis. Vancomycin pharmacokinetics was characterized using population pharmacokinetic modeling. Adsorption of vancomycin by the CytoSorb (R) was investigated as linear or saturable process. The final model was used to derive dosing recommendations based on stochastic simulations.
Results:
20 CytoSorb (R) treatments in 7 patients (160 serum samples/24 during CytoSorb (R)-treatment, all continuous infusion) were included in the study. A classical one-compartment model, including effluent flow rate of the continuous hemodialysis as linear covariate on clearance, best described the measured concentrations (without CytoSorb (R)). Significant adsorption with a linear decrease during CytoSorb (R) treatment was identified (p <0.0001) and revealed a maximum increase in vancomycin clearance of 291% (initially after CytoSorb (R) installation) and a maximum adsorption capacity of 572 mg. For a representative patient of our cohort a reduction of the area under the curve (AUC) by 93 mg/L*24 h during CytoSorb (R) treatment was observed. The additional administration of 500 mg vancomycin over 2 h during CytoSorb (R) attenuated the effect and revealed a negligible reduction of the AUC by 4 mg/L*24h.
Conclusion:
We recommend the infusion of 500 mg vancomycin over 2 h during CytoSorb (R) treatment to avoid subtherapeutic concentrations.
Cell-level systems biology model to study inflammatory bowel diseases and their treatment options
(2023)
To help understand the complex and therapeutically challenging inflammatory bowel diseases (IBDs), we developed a systems biology model of the intestinal immune system that is able to describe main aspects of IBD and different treatment modalities thereof. The model, including key cell types and processes of the mucosal immune response, compiles a large amount of isolated experimental findings from literature into a larger context and allows for simulations of different inflammation scenarios based on the underlying data and assumptions. In the context of a large and diverse virtual IBD population, we characterized the patients based on their phenotype (in contrast to healthy individuals, they developed persistent inflammation after a trigger event) rather than on a priori assumptions on parameter differences to a healthy individual. This allowed to reproduce the enormous diversity of predispositions known to lead to IBD. Analyzing different treatment effects, the model provides insight into characteristics of individual drug therapy. We illustrate for anti-TNF-alpha therapy, how the model can be used (i) to decide for alternative treatments with best prospects in the case of nonresponse, and (ii) to identify promising combination therapies with other available treatment options.
Immunodeficient mice are crucial models to evaluate the efficacy of monoclonal antibodies (mAbs). When studying mAb pharmacokinetics (PK), protection from elimination by binding to the neonatal Fc receptor (FcRn) is known to be a major process influencing the unspecific clearance of endogenous and therapeutic IgG. The concentration of endogenous IgG in immunodeficient mice, however is reduced, and this effect on the FcRn protection mechanism and subsequently on unspecific mAb clearance is unknown, yet of great importance for the interpretation of mAb PK data. We used a PBPK modelling approach to elucidate the influence of altered endogenous IgG concentrations on unspecific mAb clearance. To this end, we used PK data in immunodeficient mice, i.e. nude and severe combined immunodeficiency mice. To avoid impact of target-mediated clearance processes, we focussed on mAbs without affinity to a target antigen in these mice. In addition, intravenous immunoglobulin (IVIG) data of immunocompetent mice was used to study the impact of increased total IgG concentrations on unspecific therapeutic antibody clearance. The unspecific clearance is linear, whenever therapeutic IgG concentrations, i.e. mAb and IVIG concentrations are lower than FcRn; it can be non-linear if therapeutic IgG concentrations are larger than FcRn and endogenous IgG concentrations (e.g., under IVIG therapy). Unspecific mAb clearance of immunodeficient mice is effectively linear (under mAb doses as typically used in human). Studying the impact of reduced endogenous IgG concentrations on unspecific mAb clearance is of great relevance for the extrapolation to clinical species, e.g., when predicting mAb PK in immunosuppressed cancer patients.
Model-informed precision dosing (MIPD) is a quantitative dosing framework that combines prior knowledge on the drug-disease-patient system with patient data from therapeutic drug/ biomarker monitoring (TDM) to support individualized dosing in ongoing treatment. Structural models and prior parameter distributions used in MIPD approaches typically build on prior clinical trials that involve only a limited number of patients selected according to some exclusion/inclusion criteria. Compared to the prior clinical trial population, the patient population in clinical practice can be expected to also include altered behavior and/or increased interindividual variability, the extent of which, however, is typically unknown. Here, we address the question of how to adapt and refine models on the level of the model parameters to better reflect this real-world diversity. We propose an approach for continued learning across patients during MIPD using a sequential hierarchical Bayesian framework. The approach builds on two stages to separate the update of the individual patient parameters from updating the population parameters. Consequently, it enables continued learning across hospitals or study centers, because only summary patient data (on the level of model parameters) need to be shared, but no individual TDM data. We illustrate this continued learning approach with neutrophil-guided dosing of paclitaxel. The present study constitutes an important step toward building confidence in MIPD and eventually establishing MIPD increasingly in everyday therapeutic use.
Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis alpha monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.