#2846 Comparison of three different amikacin guidelines for pediatric patients: virtual population insight

Abstract Background and Aims Amikacin, a key aminoglycoside for treating severe pediatric infections, requires precise dosing to achieve therapeutic efficacy while minimizing nephrotoxic risks. Effective treatment depends on achieving high peak concentrations (20–80 mg/L) to ensure bacterial eradication and maintaining low trough levels (2.5–5 mg/L) to prevent toxicity. However, dosing guidelines differ across centers and countries, leading to variations in achieving these targets across pediatric populations. We present an in-silico study to compare Amikacin peak and trough levels based on different dosing guidelines. We selected guidelines from France, the United States, and the United Kingdom, representing a diverse range of dosing strategies, with many low- and middle-income countries adopting practices that fall within these ranges. Method An in-silico pharmacokinetic (PK) model, adapted from [1] and validated against clinical data from [2], was used to simulate Amikacin dosing. A virtual pediatric population (N = 1000), accounting for maturational changes in GFR, weight, and height, was generated to match the study population in [5] (median [range] age: 6 months [0.8–89], weight: 6.6 kg [2.8–22], eGFR: 116 mL/min/1.73 m² [48–290]), where eGFR was determined based on serum creatinine using the Schwartz formula. The body surface area was calculated using Mosteller's formula. Simulations in Python evaluated 24-hour dosing regimens over 7 days, following national guidelines from France [3] (dose: 30 mg/kg, peak levels >60 mg/L, and trough levels <2.5 mg/L), Stanford's Lucile Packard Children's Hospital (US) [4] (dose: 15–30 mg/kg, peak levels >20 mg/L, and trough levels <2.5 mg/L), and Sheffield Children's NHS Foundation Trust (UK) [5] (dose: 20 mg/kg, trough levels <5 mg/L). Amikacin dosing was not held when trough levels were not met in simulations. Results Amikacin peak and trough concentrations varied across dosing guidelines (Fig. 1). Median peak levels for 30 mg/kg (French guideline) ranged from 61 to 74 mg/L over the treatment days, while 15 mg/kg (UK and US) produced lower peaks of 24–29 mg/L. The 20 mg/kg dose resulted in intermediate peaks of 42–51 mg/L. Trough levels showed distinct patterns of compliance with the defined thresholds (Table 1). For the stricter <2.5 mg/L threshold, compliance decreased over the 7-day period: 99.5% to 56.6% for 15 mg/kg, 93.5% to 34.8% for 20 mg/kg, and 71.9% to 9.6% for 30 mg/kg. For the UK's less stringent <5 mg/L threshold, compliance remained higher, with 96.3% at Day 7 for 15 mg/kg, 85.6% for 20 mg/kg, and 56.6% for 30 mg/kg. By Day 7, median trough levels for 30 mg/kg exceeded 2.5 mg/L in 90.4% of the population, while 43.4% exceeded 5 mg/L. For 15 mg/kg, 43.4% of the population exceeded 2.5 mg/L, but only 3.7% exceeded 5 mg/L. Conclusion The differences in dosing guidelines result in varying treatment efficacy and nephrotoxic risks, with substantial fractions of the pediatric population not meeting trough targets across all guidelines. Moreover, without adapting the dosing during treatment, trough levels progressively increase. This highlights the need for an improved understanding of Amikacin's nephrotoxic effects in pediatric patients and the development of optimized and harmonized dosing strategies.

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