Amikacin pharmacokinetics, target attainment, and predictors in critically ill children: a retrospective cohort
Chin Chiang Toh1, Jian Lynn Lee2, Mohd Makmor Bakry1
1Centre for Quality Management of Medicines, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
Insights
Critically ill children often have altered amikacin pharmacokinetics (PK), with expanded volume of distribution (Vd) and increased clearance (CL). Standard dosing frequently leads to under-exposure, highlighting the need for PK-guided amikacin therapy in pediatric intensive care units (PICUs).
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Pediatric Critical Care Medicine
- Infectious Diseases
Background:
- Amikacin pharmacokinetics (PK) in pediatric populations exhibit significant variability.
- Standard amikacin dosing may not consistently achieve therapeutic targets in critically ill children.
- Altered drug disposition and clearance are common in pediatric intensive care unit (PICU) patients, impacting drug exposure.
Purpose of the Study:
- To quantify amikacin pharmacokinetics (PK) and early target attainment in PICU patients using third-dose therapeutic drug monitoring (TDM).
- To identify clinical covariates associated with amikacin volume of distribution (Vd) and clearance (CL) in this population.
- To assess the frequency of early target under-attainment with standard amikacin dosing.
Main Methods:
- Retrospective cohort study of 210 PICU patients receiving intravenous amikacin.
- Estimation of individual PK parameters (Vd, CL) using the Sawchuk-Zaske method based on third-dose peak and trough concentrations.
- Evaluation of clinical and laboratory covariates (age, creatinine clearance, ALT, urea) for associations with Vd and CL.
Main Results:
- Mean amikacin Vd was 0.59 L/kg and mean CL was 0.08 L/kg/h.
- Early target under-attainment was observed in 23.3% for Cmax and 7.6% for Cmin.
- Independent predictors of Vd included age, creatinine clearance (CrCl), and alanine aminotransferase (ALT); CL was associated with age, CrCl, urea, and ALT.
Conclusions:
- Critically ill children exhibit expanded Vd and increased CL, leading to inadequate early amikacin exposure with standard dosing.
- Age, CrCl, urea, and ALT are significant predictors of amikacin PK variability in PICU patients.
- PK-guided dosing and model-informed strategies are recommended to improve amikacin target attainment and individualize therapy in this high-risk population.
Abstract:
We aimed to quantify amikacin pharmacokinetics (PK) and early target attainment using routine third-dose therapeutic drug monitoring (TDM) in pediatric intensive care unit (PICU) patients and to identify clinical covariates associated with volume of distribution (Vd) and clearance (CL). We conducted a retrospective cohort study of PICU patients who received intravenous amikacin between January 2022 and December 2023. Individual PK parameters were estimated using third-dose peak and trough concentrations via the Sawchuk-Zaske method. Clinical and laboratory covariates were evaluated for associations with Vd and CL. Among 210 patients, mean Vd was 0.59 ± 0.30 L/kg and mean CL was 0.08 ± 0.03 L/kg/h. Early target under attainment was frequent, with 23.3% of and 7.6% of values outside therapeutic targets. Independent predictors of Vd included age, creatinine clearance (CrCl), and alanine aminotransferase (ALT), while CL was independently associated with age, CrCl, urea, and ALT. Conclusion: Critically ill children demonstrate expanded Vd and increased CL, contributing to inadequate early amikacin exposure under standard dosing. Early PK-guided dosing and model-informed strategies may improve target attainment and individualized therapy in this high-risk population. What is Known: Amikacin PK in children is variable, and standard dosing may not consistently achieve therapeutic targets. Critically ill pediatric patients often experience altered drug disposition and clearance, which can affect amikacin exposure and response. What is New: This study quantified amikacin PK parameters in critically ill children receiving routine TDM in the PICU. Expanded Vd and increased CL were identified, with age, CrCl, urea, and ALT associated with variability in amikacin PK.
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