Aysenur Yaliniz 1,2, Laurence Clouâtre 2, Thomas Pincez 3,4, Niina Kleiber 3,4, Yves Pastore 3,4, Julie Autmizguine 3,4,5, Amélie Marsot 1,2,4
1 Laboratoire de Suivi Thérapeutique Pharmacologique et Pharmacocinétique, Faculty of Pharmacy, Université de Montréal (, Canada), 2 Faculty of Pharmacy, Université de Montréal (, Canada), 3 Department of Pediatrics, Faculty of Medicine, Université de Montréal (, Canada), 4 Research center, Centre Hospitalier Universitaire Sainte-Justine (, Canada), 5 Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal (, Canada)
Introduction: Infections are the leading cause of mortality among patients with sickle cell disease (SCD) worldwide. [1] This population is at high risk of severe infections such as sepsis and meningitis, frequently requiring antibiotic therapy. [1, 2] In Canada, ceftriaxone is one of the most commonly used antibiotics in patients with SCD, largely due to its activity against prevalent pathogens and its long half-life, allowing once-daily administration. [1, 3] The pharmacodynamic (PD) efficacy target for ceftriaxone is the proportion of the dosing interval during which free (unbound) drug concentrations remain above the pathogen’s minimum inhibitory concentration (MIC), commonly defined as at least 60% fT > MIC. [4] Pediatric patients with SCD present important age- and disease-related characteristics that may significantly affect ceftriaxone pharmacokinetics (PK). As a multisystem disease involving several organs, including the kidneys, the primary elimination route of ceftriaxone, SCD may further alter drug disposition. [2, 3] Moreover, given ceftriaxone’s extensive and saturable albumin binding, differences in unbound fraction may significantly influence its PK and target attainment. [5] Therefore, the doses required in this pediatric subpopulation may differ from those used in routine clinical practice. Inappropriate dosing may lead to subtherapeutic exposure, treatment failure, antimicrobial resistance or toxicity. Population pharmacokinetic (popPK) modeling can help characterize ceftriaxone PK in these patients and thereby inform the optimization of dosing regimens to improve target attainment.
Objectives: This project aims to evaluate published pediatric popPK models of ceftriaxone to identify the model with the best predictive performance in Quebec patients with SCD and to propose optimized dosing regimens.
Methods: Data were obtained from a prospective study of pediatric patients with sickle cell disease conducted at the Centre Hospitalier Universitaire Sainte-Justine (CHUSJ) in Montreal, between March 2022 and July 2023. All patients received intravenous or intramuscular ceftriaxone for suspected or confirmed infection. Blood samples were collected using an opportunistic sampling strategy. Total plasma concentrations were quantified using a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay. A literature review was conducted using the PubMed database to identify published popPK models of ceftriaxone in pediatric patients developed with nonlinear mixed-effects modeling. The identified models were transcribed to allow external evaluation and assess their predictive performance. Prediction errors (PE%) were calculated by comparing model-predicted (PRED) and observed (DV) concentrations according to the following equation: [(PRED-DV)/DV] x 100%. [6] Bias and imprecision were assessed using the median PE% and median absolute PE%, respectively. [6] Adequate predictive performance was defined by a bias between ±20% and an imprecision ≤30%. [6] The popPK analysis was conducted using NONMEM v7.6 (ICON Development Solutions) with the Pirana v23.10.1 interface. Data visualization and statistical analyses were conducted in R v4.4.2 (R Project for Statistical Computing) using the RStudio v2024.09.1 interface.
Results: A total of 17 patients were enrolled, including 11 females and 6 males. Their median [range] age, body weight and serum creatinine were 4.92 [0.25-9.83] years, 19.9 [6.02-28.3] kg and 42 [33-58] mg/dL, respectively. Ceftriaxone doses ranging from 46.1 to 84.6 mg/kg were administered, primarily intravenously as bolus injections or short infusions, with only one patient receiving intramuscular administration. Twenty-one samples were collected, with one to two per patient. Quantified concentrations ranged from 7.67 to 389 mg/L and were associated with post-administration times ranging from 0.62 to 22.3 h. The literature review identified eight pediatric popPK models for ceftriaxone, published from 2010 to 2024. [7-14] Following external evaluation, two models demonstrated satisfactory predictive performance according to the preestablished criteria: Hartman et al. [12] and Girdwood et al. [13]. Both were two-compartment models developed in critically ill populations, with body weight and renal function as covariates. [12, 13] Bias and imprecision were -16.0% and 23.2% for the Hartman et al. model [12], and -0.63% and 13.9% for the Girdwood et al. model [13], respectively. The latter was therefore selected as the best-performing model. [13]
Conclusions: This study identified two ceftriaxone popPK models suitable for pediatric patients with SCD in Quebec. Body weight and renal function appear to be key covariates influencing ceftriaxone PK in this population, consistent with the central role of body size in pediatrics and the drug’s predominant renal elimination. Future work will involve model-based simulations to define an optimized dosing regimen that ensures therapeutic target attainment in children with SCD.
References:
[1] Canadian Haemoglobinopathy Association. Consensus Statement on the Care of Patients with Sickle Cell Disease in Canada,2015.
[2] Ware RE et al. Sickle cell disease. Lancet. 2017;390(10091):311-23.
[3] Seddon M et al. Pharmacokinetics of Ro 13-9904, a broad-spectrum cephalosporin. Antimicrob Agents Chemother. 1980;18(2):240-2.
[4] Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis.1998;26(1):1-10.
[5] Pfizer Canada. Ceftriaxone Sodium for Injection BP [PRODUCT MONOGRAPH].2022.
[6] Miyabe-Nishiwaki T et al. Evaluation of the predictive performance of a pharmacokinetic model for propofol in Japanese macaques. J Vet Pharmacol Ther.2013;36(2):169-73.
[7] Iida S et al. Indications for a ceftriaxone dosing regimen in Japanese paediatric patients using population pharmacokinetic/pharmacodynamic analysis and simulation. J Pharm Pharmacol. 2011;63(1):65-72.
[8] Standing JF et al. Dosing of Ceftriaxone and Metronidazole for Children With Severe Acute Malnutrition. Clin Pharmacol Ther. 2018;104(6):1165-74.
[9] Mukap M et al. Validation of a Dried Blood Spot Ceftriaxone Assay in Papua New Guinean Children with Severe Bacterial Infections. Antimicrob Agents Chemother. 2018;62(10).
[10] Khan MW et al. Population pharmacokinetics and dose optimization of ceftriaxone for children with community-acquired pneumonia. Eur J Clin Pharmacol. 2020;76(11):1547-56.
[11] Wang YK et al. Optimal Dosing of Ceftriaxone in Infants Based on a Developmental Population Pharmacokinetic-Pharmacodynamic Analysis. Antimicrob Agents Chemother. 2020;64(11).
[12] Hartman SJF et al. Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study. Clin Pharmacokinet. 2021;60(10):1361-72.
[13] Tang Girdwood S et al. Population Pharmacokinetic Modeling of Total and Free Ceftriaxone in Critically Ill Children and Young Adults and Monte Carlo Simulations Support Twice Daily Dosing for Target Attainment. Antimicrob Agents Chemother. 2022;66(1):e0142721.
[14] Boast A et al. Population pharmacokinetic modeling of ceftriaxone in cerebrospinal fluid in children: should we be using once- or twice-daily dosing for meningitis? Antimicrob Agents Chemother. 2024;68(11):e0074724.
Reference: PAGE 34 (2026) Abstr 12067 [www.page-meeting.org/?abstract=12067]
Poster: Drug/Disease Modelling - Paediatrics