Seef Abdalla1,2, William Royer1, Agathe Béranger1,3, Claire Heilbronner1,3, Vanessa Lopez-Lopez1,4, Pierre-Louis Léger1,5, Romain Berthaud1,6, David Drummond1,7, Martin Castelle1,8, Elsa Kermorvant1,9, Jean-Marc Tréluyer1,2, Mehdi Oualha1,3, Déborah Hirt1,2
1Université Paris Cité, Inserm, Pharmacologie et évaluations des thérapeutiques chez l'enfant et la femme enceinte, 2Service de pharmacologie périnatale, pédiatrique et adulte, AP-HP, Hôpital Cochin, F-75014 Paris, Hôpital Européen Georges Pompidou, 3Service de réanimation et surveillance continue médicochirurgicales pédiatriques, AP-HP, Hôpital Necker Enfants malades, 4Service d'Anesthésie réanimation pédiatrique et obstétricale, AP-HP, Hôpital Necker Enfants malades, 5Service de Réanimation néonatale pédiatrique, AP-HP, Hôpital Armand-Trousseau, 6Service de Néphrologie pédiatrique, AP-HP, Hôpital Necker Enfants malades, 7Service de Pneumologie et allergologie pédiatriques, AP-HP, Hôpital Necker Enfants malades, 8Service d'Immuno-Hématologie et Rhumatologie pédiatriques, AP-HP, Hôpital Necker Enfants malades, 9Service de Néonatalogie et réanimation néonatale, AP-HP, Hôpital Necker Enfants malades
Introduction: Critically ill patients are often subject to important pharmacokinetic alterations that can lead to under- or over-exposure. In addition, children and neonates undergo physical growth and organ maturation that can alter drug exposure if no dose adjustments are made, especially children with sickle cell disease who usually also experience organ dysfunctions.[1] Cefotaxime is one of the most prescribed antibiotics in the pediatric intensive care unit.[2,3] Methods: Based on real-life setting data from therapeutic drug monitoring in critically ill children and neonates, we performed a pharmacokinetic analysis of cefotaxime and its metabolite desacetyl-cefotaxime via a population approach, using Monolix software.[4] For cefotaxime concentrations, one- or two-compartment models were tested. Five hundred Monte-Carlo simulations of cefotaxime trough and steady-state concentrations were computed. Several doses through 30-minutes infusion every 4 hours, every 6 hours or through continuous infusion were tested, and simulated concentrations were compared to the following pharmacological targets: free concentration above 4 times the minimum inhibitory concentration 100% of the time (100% fT>4×MIC) and trough concentration (Ct) or steady-state concentration (CSS) below 60 mg/L. Simulations were done with MRGSOLVE package in R software.[5] Results: Seven hundred and ninety-seven observations of cefotaxime and desacetyl-cefotaxime were collected from 242 children and neonates. The cefotaxime data were best described by a two-compartment model with first-order absorption and elimination. A supplemental compartment was linked to the cefotaxime central compartment to describe the pharmacokinetics of desacetyl-cefotaxime. Parameters of the model were cefotaxime central volume of distribution (V1), peripheral volume of distribution (V2), inter-compartmental clearance (Q), non-metabolic clearance (CL), apparent metabolization rate constant (CLm/Vm), and metabolite elimination rate (kem). Allometric scaling by body weight with fixed exponents for volumes and clearances was added to the model. The addition of estimated glomerular filtration rate (eGFR calculated with the Schwarz formula) on CL and kem was found to be significant in the model. Cefotaxime non-metabolic elimination and desacetyl-cefotaxime elimination were on average 60% higher in patients with augmented renal clearance (eGFR > 200 mL/min). The influence of sickle cell disease on CL was also significant in the model. On average, cefotaxime non-metabolic clearance increased by 35% in patients with sickle cell disease. Post-menstrual age was included to describe organ maturation functions in neonates using a Hill model. In term newborns, 50% of adult elimination capacities was achieved within the first week of life. Based on the desacetylcefotaxime/cefotaxime AUC0-24h ratio predicted by the model, the median desacetyl derivative formation accounted for 26 % of the total cefotaxime dose administered. Simulations showed that the probability of target attainment was almost systematically better with a continuous perfusion. Doses ranging from 100 to 300 mg/kg/day were suggested, according to bodyweight, sickle cell status and eGFR. Conclusion: A cefotaxime/desacetyl-cefotaxime population PK model was successfully developed for critically ill children and neonates, and allowed dose guidance, taking into account patient characteristics and conditions.
[1] Maksoud E, Koehl B, Facchin A, Ha P, Zhao W, Kaguelidou F, et al. Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease. Antimicrob Agents Chemother 2018;62:e00637-17. https://doi.org/10.1128/AAC.00637-17. [2] Kosmidis J, Stathakis Ch, Mantopoulos K, Pouriezi T, Papathanassiou B, Daikos GK. Clinical pharmacology of cefotaxime including penetration into bile, sputum, bone and cerebrospinal fluid. J Antimicrob Chemother 1980;6:147–51. https://doi.org/10.1093/jac/6.suppl_A.147. [3] Béranger A, Oualha M, Urien S, Genuini M, Renolleau S, Aboura R, et al. Population Pharmacokinetic Model to Optimize Cefotaxime Dosing Regimen in Critically Ill Children. Clin Pharmacokinet 2018;57:867–75. https://doi.org/10.1007/s40262-017-0602-9. [4] Monolix 2024R1, Lixoft SAS, a Simulations Plus company. 2024. [5] Baron K. Simulate from ODE-Based Models 2024. https://mrgsolve.org/.
Reference: PAGE 33 (2025) Abstr 11313 [www.page-meeting.org/?abstract=11313]
Poster: Drug/Disease Modelling - Paediatrics