Clinical pharmacokinetics · 2026
Nomograms for Therapeutic Drug Monitoring of High-Dose Amikacin in Critically Ill Patients: Insights from a Population Pharmacokinetic Analysis and Dosing Simulation.
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Nguyen Thi Cuc, Le Dinh Van, Nguyen Hoang Anh, Nam Tien Nguyen Tran, Nguyen Thi Hong Ngoc, Vu Dinh Hoa, Nguyen Hoang Anh, Pham Hong Nhung, Nguyen Cong Tan, Nguyen Dang Minh Vuong, Pham The Thach, Do Ngoc Son, Dang Quoc Tuan, Dao Xuan Co, Alffenaar Jan-Willem C
Аннотация
BACKGROUND AND OBJECTIVE: This study evaluated the probability of pharmacokinetic/pharmacodynamic efficacy target attainment and developed a dosing interval identification nomogram to minimize toxicity risks of high-dose amikacin.
METHODS: Therapeutic drug monitoring was performed in critically ill patients receiving high-dose (30 mg/kg) amikacin intravenously. Population pharmacokinetic modeling and Monte Carlo simulation were performed in NONMEM® 7.5.1. The probability of target attainment and the cumulative fraction of response for the local Klebsiella pneumoniae population were assessed using maximum concentration/minimum inhibitory concentration ≥ 8 as the efficacy target. Nomograms stratified by the renal function group were established to guide dosing intervals to avoid exceeding the toxicity minimum concentration threshold of 2.5 mg/L.
RESULTS: A total of 251 patients with 488 amikacin concentrations were included. The amikacin pharmacokinetics was best described by a two-compartment model. The creatinine clearance and adjusted body weight were significant covariates for clearance and the central volume of distribution, respectively. Amikacin 30 mg/kg achieved a probability of target attainment > 90% for minimum inhibitory concentrations < 8 mg/L and around 80% for minimum inhibitory concentrations of 8 mg/L. This regimen showed a cumulative fraction of response of 63.5% for K. pneumoniae, while attaining a cumulative fraction of response of 96.8% for susceptible isolates. The 30-mg/kg nomograms in patients with creatinine clearance < 60 and ≥ 60 mL/min showed accurate dosing intervals with around 90% of virtual patients for the post-infusion period from 20 to 32 h and from 6 to 32 h, respectively.
CONCLUSIONS: Nomogram-aided dosing interval adjustment of high-dose amikacin (30 mg/kg) maximized the efficacy and safety target attainment for critically ill patients with infections caused by susceptible K. pneumoniae.
METHODS: Therapeutic drug monitoring was performed in critically ill patients receiving high-dose (30 mg/kg) amikacin intravenously. Population pharmacokinetic modeling and Monte Carlo simulation were performed in NONMEM® 7.5.1. The probability of target attainment and the cumulative fraction of response for the local Klebsiella pneumoniae population were assessed using maximum concentration/minimum inhibitory concentration ≥ 8 as the efficacy target. Nomograms stratified by the renal function group were established to guide dosing intervals to avoid exceeding the toxicity minimum concentration threshold of 2.5 mg/L.
RESULTS: A total of 251 patients with 488 amikacin concentrations were included. The amikacin pharmacokinetics was best described by a two-compartment model. The creatinine clearance and adjusted body weight were significant covariates for clearance and the central volume of distribution, respectively. Amikacin 30 mg/kg achieved a probability of target attainment > 90% for minimum inhibitory concentrations < 8 mg/L and around 80% for minimum inhibitory concentrations of 8 mg/L. This regimen showed a cumulative fraction of response of 63.5% for K. pneumoniae, while attaining a cumulative fraction of response of 96.8% for susceptible isolates. The 30-mg/kg nomograms in patients with creatinine clearance < 60 and ≥ 60 mL/min showed accurate dosing intervals with around 90% of virtual patients for the post-infusion period from 20 to 32 h and from 6 to 32 h, respectively.
CONCLUSIONS: Nomogram-aided dosing interval adjustment of high-dose amikacin (30 mg/kg) maximized the efficacy and safety target attainment for critically ill patients with infections caused by susceptible K. pneumoniae.