Pharmacokinetics of cefotaxime in intensive care patients: exploration of the sources of variability with a population model
A. Deschamps(1,2*), L. Velly(3), E. Jouve(2), R. Guilhaumou(2), F. Gattacceca(1)
(1) Inria-Inserm COMPO Team, Centre Inria Sophia Antipolis - Méditerranée, Cancer Research Center of Marseille, Inserm U1068, CNRS UMR7258, Aix-Marseille University UM105, Institut Paoli-Calmettes, Marseille, France. (2) Aix Marseille Univ, APHM, INSERM, CIC CPCET Service de Pharmacologie Clinique et Pharmacovigilance, INS Inst Neurosci Syst, Marseille, France Aix-Marseille University, (3) Department of Anaesthesiology and Critical Care Medicine, University Hospital Timone, Marseille, France.
Objectives: Cefotaxime is a beta-lactam antibiotics commonly used in intensive care unit (ICU) patients. In this population, pathophysiological modifications induce a high inter- and intra-individual pharmacokinetic variability which can result in supra or sub-therapeutic concentrations of cefotaxime. Indeed, it has recently been shown that the risk of not meeting the PK/PD target was particularly high with cefotaxime in ICU patients1. To date, only one population PK study has been performed in this context2. A better understanding of the sources and correlates of PK variability in ICU patients is then required to perform cefotaxime a priori dose adjustment.
Methods: In a prospective, observational study, adult ICU patients (October 2015 - May 2017) were treated with a loading dose (2-4g/0.5h) followed by a continuous infusion (1-24g/24h) of cefotaxime. Cefotaxime concentrations 30 minutes after the loading dose, during the continuous infusion at day 1, 4 and 7 after drug initiation, and 4 hours after the end of the infusion, were measured by a validated HPLC-UV method. Demographic, clinical and biological data were collected at inclusion and throughout the study. Data were analysed by nonlinear mixed-effects modeling using MONOLIX version 2021R2. Data below the limit of quantification were treated as left-censored. The impact of baseline values of covariates on PK parameters was evaluated using the stepwise covariate model procedure. Continuous covariates were included using a power model.
Results: The study included 76 ICU hospitalized patients (31 females, 45 males, age = 57,5 ± 17,6 years). 251 cefotaxime plasma concentrations were available for PK analysis. A one-compartment model with linear elimination and proportional residual error best described the data. Inclusion of the impact of uraemia, albuminemia and estimated glomerular filtration rate (eGFR) on cefotaxime clearance significantly improved the model and reduced the unexplained inter-individual variability of clearance from 54 to 36 %. The typical values of clearance and volume of distribution were 5.02 L/h and 22.72 L respectively for a patient with median values of covariates. Higher albuminemia and higher eGFR were associated to a higher cefotaxime clearance with a power of 0.79 and 0.34 respectively, while higher uraemia was associated to a lower cefotaxime clearance, with a power of -0.26.
Conclusions: A population PK model was developed in order to describe the PK of cefotaxime and identify the main sources of its variability in the context of adult ICU patients. While the impact of albuminemia and eGFR on cefotaxime clearance had been identified previously2, our work allowed to characterize the relationship between cefotaxime clearance and uraemia. The current model is a first step toward a thorougher exploration of the influence of covariates and of their fast evolution in ICU patients on the PK of cefotaxime. Since some covariate effects might be similar for several β-lactams3, our model might be extended to other β-lactams in order to optimize a priori dose adjustment in the context of switches between molecules.
References:
[1] Smekal, A.-K.; Furebring, M.; Eliasson, E.; Lipcsey, M. Low Attainment to PK/PD-Targets for β-Lactams in a Multi-Center Study on the First 72 h of Treatment in ICU Patients. Sci. Rep. 2022, 12 (1), 21891. https://doi.org/10.1038/s41598-022-25967-9.
[2] Roelofsen, E. E.; Abdulla, A.; Muller, A. E.; Endeman, H.; Gommers, D.; Dijkstra, A.; Hunfeld, N. G. M.; de Winter, B. C. M.; Koch, B. C. P. Dose Optimization of Cefotaxime as Pre‐emptive Treatment in Critically Ill Adult Patients: A Population Pharmacokinetic Study. Br. J. Clin. Pharmacol. 2023, 89 (2), 705–713. https://doi.org/10.1111/bcp.15487.
[3] Delattre, I. K.; Musuamba, F. T.; Jacqmin, P.; Taccone, F. S.; Laterre, P.-F.; Verbeeck, R. K.; Jacobs, F.; Wallemacq, P. Population Pharmacokinetics of Four β-Lactams in Critically Ill Septic Patients Comedicated with Amikacin. Clin. Biochem. 2012, 45 (10–11), 780–786. https://doi.org/10.1016/j.clinbiochem.2012.03.030.