S Bui1, A Facchin2,3,4, P Ha2, S Bouchet5, S Leroux2, F Nacka1, M Fayon1, E Jacqz-Aigrain2,4,6. 1. Centre d'Investigation Clinique (CIC1401), Centre de Ressources et de Compétences de la Mucoviscidose (CRCM), Centre de Recherche Cardio-thoracique de Bordeaux (U1045), Université de Bordeaux, Centre Hospitalier Universitaire de Bordeaux Groupe hospitalier Pellegrin, Bordeaux, France. 2. Département de Pharmacologie Pédiatrique et Pharmacogénétique, Centre Hospitalier Universitaire Robert Debré APHP, Paris, France. 3. Service de Pharmacie, Centre hospitalier Intercommunal Robert Ballanger, Aulnay-sous-Bois, France. 4. Université de Paris, Paris, France. 5. Département de Pharmacologie et de toxicologie, Centre Hospitalier Universitaire de Bordeaux, Groupe hospitalier Pellegrin, Bordeaux, France. 6. Centre d'Investigation Clinique (CIC1426), Centre Hospitalier Universitaire Robert Debré APHP, Paris, France.
Abstract
BACKGROUND: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections. OBJECTIVES: To characterize the population pharmacokinetics of ceftazidime in critically ill children, identify covariates that affect drug disposition and evaluate the current dosing regimens. METHODS: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software. RESULTS: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T>MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children. CONCLUSIONS: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children.
BACKGROUND: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections. OBJECTIVES: To characterize the population pharmacokinetics of ceftazidime in critically illchildren, identify covariates that affect drug disposition and evaluate the current dosing regimens. METHODS: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software. RESULTS: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T>MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children. CONCLUSIONS: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children.
Authors: Ronaldo Morales Junior; Gabriela Otofuji Pereira; Gustavo Magno Baldin Tiguman; Vanessa D'Amaro Juodinis; João Paulo Telles; Daniela Carla de Souza; Silvia Regina Cavani Jorge Santos Journal: Front Pediatr Date: 2022-03-10 Impact factor: 3.418