Arkadiusz Adamiszak (1,2), Agnieszka Bienert (1)
(1) Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Poland, (2) Doctoral School, Poznan University of Medical Sciences, Poland
Introduction/Objectives: Ceftaroline is a fifth-generation cephalosporin reserved for treating resistant gram-positive and gram-negative bacteria [1]. Currently, no dosing standards have been recommended by The European Committee on Antimicrobial Susceptibility Testing (EUCAST) or Stanford Health Care Antimicrobial Dosing Reference Guide for ceftaroline in patients undergoing continuous renal replacement therapy (CRRT) [2,3]. This study aimed to develop a preliminary population pharmacokinetic (PopPK) model and investigate dosages for CRRT intensive care unit (ICU) patients.
Methods: Pharmacokinetic and clinical data were obtained retrospectively from 4 articles describing ICU patients treated with 400-600 mg of ceftaroline in 1h infusion [4-7]. The data from the graphs were extracted using WebPlotDigitizer [8]. Ceftaroline concentration-time data were analysed using PopPK modelling according to the SAEM algorithm for non-linear mixed effects models implemented in the Monolix [9]. Model selection was based on goodness-of-fit criteria such as corrected Bayesian Information Criteria (BICc), the objective function value (OFV) defined as −2×Log Likelihood of the data, the precision of the parameter estimates, and diagnostic plots. We assumed a priori a two-compartment model with linear elimination [1]. Any clinical variables were examined as potential covariates using a stepwise covariate model procedure (SCM). Simulations of dosing regimens were performed in Simulx [10]. We tested 200/300/400/600 mg in a 1h infusion every 12 hours and a 2h infusion every 8 hours as standard and high dosages according to SmPC, respectively [11]. For each combination, we simulated 2500 patients as 50 patients in a group replicated 50 times. For the probability of target attainment (PTA) analysis, we assumed 100%fT>MIC and 100%fT>4xMIC as standard and high PK/PD targets, respectively [12]. The PTA ≥ 90% for MIC values up to 4 mg/L was considered an acceptable probability of success [13]. The free fraction of ceftaroline was calculated based on a percentage (~20%) of protein binding mentioned in SmPC [11].
Results: The study included 33 adult ICU patients (12 female, 21 male) and 296 plasma samples, of which 26 were from 4 CRRT patients. The median (range) of testing continuous covariates for age was 55.0 years (21.0 – 77.0), weight was 77.0 kg (49.0 – 111.8), creatinine clearance was 169.0 mL/min (58.3 – 309.0), and albumin level was 2.7 g/dL (2.0 – 3.2). The mean population parameter estimates (RSE%) for clearance (CL) was 11.16 L/h (4.87%), central compartment volume (V1) was 20.55 L (3.53%), inter-compartmental clearance (Q) was 6.96 L/h (15.2) and peripheral compartment volume (V2) was 18.13 L (16.5). Inclusion of the impact of creatine clearance and CRRT (as a categorical variable) on Cl and CRRT on V1 significantly improved model fitting and decreased the unexplained inter-individual variability of Cl from 38% to 23% and V1 from 11% to 4%. The remaining coefficients of variation (CV) were 40% for Q and 77% for V2. The residual error was estimated using a combined error model. According to simulations for 100%fT>MIC, ICU patients undergoing CRRT are able to achieve assumed PTA ≥ 90% using already approved dosages. Up to MIC equal to 0.5 mg/L, 200 mg/12h in a 1h infusion, for MIC 1, 400 mg/12h in a 1h infusion, and MIC 2 and 4, 300 and 600 mg/8h in 2h infusion, respectively, is required. In turn, achieving the PTA ≥ 90% for 100%fT>4xMIC using approved dosages is possible only for MIC up to 1 mg/L and for MIC 0.0625 and 0.125, 200 mg/12h in 1h infusion, MIC 0.25, 400 mg/12h in 1h infusion, MIC 0.5, 300 mg/8h in 2h infusion, and MIC 1, 600 mg/8h in 2h infusion is required. In the case of MIC 2 and 4, with the highest approved dosage (600 mg/8h in 2h infusion), PTA ≥ 90% was achieved in 22% and 0% of simulated patients, respectively.
Conclusions: CRRT affects the pharmacokinetics of ceftaroline, so dose adjustments are necessary. Doses approved to date are insufficient to achieve PTA ≥ 90% for a high PK/PD target (100%fT>4xMIC) and MIC ≥ 2 mg/L, which creates a need to consider higher total dosages or continuous infusion. Our results should be used with caution, given the scarce number of CRRT patients included in the model. Increasing the number of patients is a chance to integrate a total effluent flow rate during CRRT as a covariate, which may result in more precise dosage simulations and decreased model uncertainty.
References:
[1] Steed, M. E. et al. Pharmacotherapy 30, 375–389 (2010)
[2] EUCAST Clinical breakpoints 2024 (v 14.0) (https://www.eucast.org/clinical_breakpoints)
[3] Stanford Antimicrobial Safety & Sustainability Program (https://med.stanford.edu/bugsanddrugs/guidebook.html)
[4] Alarcia-Lacalle, A. et al. Pharmaceutics 13, 959 (2021)
[5] Chauzy, A. et al. J Antimicrob Chemother 77, 3173–3179 (2022)
[6] Kalaria, S. et al. Pharmacotherapy 41, 205–211 (2021)
[7] Chauzy, A. et al. Journal of Antimicrobial Chemotherapy 74, 675–681 (2019)
[8] Rohatgi, A. WebPlotDigitizer User Manual Version 4.6 (2022)
[9] Monolix 2023R1, Lixoft SAS, a Simulations Plus company.
[10] Simulx 2023R1, Lixoft SAS, a Simulations Plus company.
[11] Zinofro (SmPC).
[12] Gatti, M. et al. Clinical Pharmacokinetics 60, 1271 (2021)
[13] Lewis, S. J. et al. BMC Nephrol 25, 73 (2024)
Reference: PAGE 32 (2024) Abstr 11166 [www.page-meeting.org/?abstract=11166]
Poster: Drug/Disease Modelling - Infection