Jordan Brooks 1, Tiffany Lee 1, Ron Keizer 1
1 Insightrx (San Francisco, USA)
Introduction: Cefepime is a broad-spectrum beta-lactam antibiotic critical for treating severe gram-negative infections, including Pseudomonas aeruginosa. Optimal dosing requires balancing efficacy targets (free concentration time above minimum inhibitory concentration – fT>MIC) with neurotoxicity risk, particularly in patients with impaired renal function [1, 2]. Extended infusions and therapeutic drug monitoring have been proposed to optimize therapy [3], but implementation barriers limit adoption. This simulation study evaluates MIPD strategies for cefepime across renal function strata and infusion durations.
Objectives: To evaluate the impact of model-informed precision dosing (MIPD) strategies on cefepime target attainment and neurotoxicity risk across renal function strata and infusion durations using population pharmacokinetic simulations.
Methods: We simulated cefepime pharmacokinetics in adult populations using demographics from NHANES 2019-2020, stratified by creatinine clearance (CrCl). Three dosing approaches were compared: (1) standard nomogram, (2) model-based initial dose without adjustments, and (3) MIPD with concentration sampling and dose optimization targeting 99% fT>MIC of the dosing interval. Two population PK models were employed: Jonckheere et al. [1] for simulation and An et al. [2] for MAP Bayesian estimation. Target attainment for fT>MIC (MIC = 8 mg/L for Pseudomonas aeruginosa) and neurotoxicity risk based on steady-state trough concentrations were assessed across infusion durations (short vs. extended) and sampling strategies (peak-trough, trough-only, random). Doses were optimized while intervals remained fixed by renal function. The Boschung-Pasquier exposure-response model [3] was used to estimate neurotoxicity probability based on trough concentration, with number needed to treat (NNT) calculations across scaled risk scenarios. Open-source R packages were utilized include nhanesA for data extraction, InsightRX developed packages including PKPDsim for PK simulation, PKPDmap for MAP Bayesian estimation, and mipdtrial for dynamic dose adjustment simulations [4].
Results: MIPD with concentration sampling and dose optimization targeting achieved 94% target attainment (percentage achieving >95% fT>MIC) across all renal function groups while maintaining lower steady-state troughs than standard nomograms. Model-based initial dosing without subsequent adjustments achieved 81% target attainment but resulted in underexposure in patients with CrCl <60 mL/min, where 19% of patients had concentrations below the MIC for >95% of the dosing interval. Standard nomograms achieved reasonable efficacy targets but produced higher troughs, particularly in subpopulations with reduced renal function (CrCl <60 mL/min), raising toxicity concerns. Random sampling for dose optimization performed comparably to fixed peak-trough sampling, offering practical implementation advantages. Neurotoxicity risk analysis demonstrated that MIPD yielded a NNT of 25 to prevent one cefepime-induced neurotoxicity event compared to standard nomograms independent of renal function, even when scaling the base neurotoxicity model to a 50% more conservative association. The gradient analysis confirmed that MIPD approaches maintained superior risk-benefit profiles across varying neurotoxicity assumptions. Conclusions: MIPD with concentration sampling and dose optimization targeting provides a practical framework to optimize cefepime dosing, balancing efficacy and toxicity. MIPD targeting offers superior outcomes compared to standard nomograms or model-based initial dosing alone, particularly in patients with impaired renal function. These findings warrant prospective validation and highlight the need for continued population PK model refinement as real-world cefepime pharmacokinetic data become available. References: References: [1] Jonckheere S, De Neve N, Verbeke J, et al. Target-Controlled Infusion of Cefepime in Critically Ill Patients. Antimicrob Agents Chemother. 2019;64(1):e01552-19. [2] An G, Creech CB, Wu N, et al. Population pharmacokinetics and target attainment analyses to identify a rational empirical dosing strategy for cefepime in critically ill patients. J Antimicrob Chemother. 2023;78(6):1460-70. [3] Boschung-Pasquier L, Atkinson A, Kastner LK, et al. Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study. Clin Microbiol Infect. 2020;26(3):333-9. [4] InsightRX. InsightRX GitHub repositories. GitHub. 2025 [cited 2026 Feb 20]. Available from: https://github.com/InsightRX.
Reference: PAGE 34 (2026) Abstr 12052 [www.page-meeting.org/?abstract=12052]
Poster: Drug/Disease Modelling - Infection