Population Pharmacokinetic Modeling of Gentamicin in Pediatrics

Abstract

The primary objective of this work was to characterize the pharmacokinetics (PK) of gentamicin across the whole pediatric age spectrum from premature neonates to young adults with a single model by identifying significant clinical predictors. A nonlinear mixed‐effect population PK model was developed with retrospective therapeutic drug‐monitoring data. A total of 6459 drug concentration measurements from 3370 hospitalized patients were collected for model building (n = 2357) and evaluation (n = 1013). In agreement with previously reported models, a 2‐compartment model with first‐order elimination best described the drug PK. Patient‐specific factors significantly impacting gentamicin clearance included fat‐free mass, postmenstrual age, and serum creatinine (SCr). Based on our model, the deviation of the individual SCr from the age‐dependent expected mean SCr value (SCrM) can result in a 40% lower clearance in a patient with renal impairment than that in a patient with normal kidney function, with SCrM:SCr ratios between 0.16 and 3.2 in this study. Consistent with the known age‐dependent changes of the proportion of extracellular water in body weight, the inclusion of the impact of extracellular water maturation on the central volume of distribution was found to improve the model fitting significantly. In comparison with other published models, model evaluation suggested the developed model was the least biased and physiologically most representative. These results will be used to inform individualized initial dosing strategies and serve as a prior PK model for Bayesian updating and forecasting as individual clinical observations become available.

Optimizing gentamicin dosing in different pediatric age groups using population pharmacokinetics and Monte Carlo simulation

“…Dosing recommendations from our study were found to achieve PTA values of at least 90% when the MIC of gentamicin against the organism was 1 mg/L or lower while maintaining trough concentrations below the nephrotoxicity threshold of 1 mg/L, likely as a result of normal kidney functions in our population derived model. Consistent with our finding, a recent model that predicted dosing with a target to achieve a gentamicin C max of 10 mg/L under a once daily dosing regimen suggested that dosing requirements decrease from birth (4 mg/kg) up to 18 years of age (2.7 mg/kg) [ 5 ]. Similar dosing recommendations were suggested by Lopez et al, despite including critically ill patients [ 11 ].…”

“…Most of the population PK studies of gentamicin in pediatrics focused on neonates and only a couple of studies included pediatric patients with age groups similar to our population [ 5 , 11 , 14 , 15 ]. More recently, Wang et al included physiological maturation of the extracellular weight into the model and estimated the values of clearance and central volume of distribution to be 4.6 L/hr.…”

“…Two recent studies have also evaluated gentamicin PK in pediatrics [ 4 , 5 ]. The first study employed a one-compartment model to characterize gentamicin PK followed by Monte Carlo simulation to evaluate the optimal dosing for all patients aged 1 month to 12 years at different MICs.…”

Differences in the Pharmacokinetics of Gentamicin between Oncology and Nononcology Pediatric Patients

“…PK parameter estimates in this study are in agreement with those of another recent study involving more than 2,000 pediatric patients (PMA range, 21 to 1,026 weeks), where the following PK parameter estimates were reported: CL of 4.57 liters/h/70 kg TBW, V 1 of 18.1 liters/70 kg TBW, Q of 1.07 liters/h/70 kg TBW, and V 2 of 17.1 liters/70 kg TBW (15). In our study, oncology patients had lower V 1 (18.1 liters/57.5 kg NFM) and Q (0.57 liters/h/ 56.1 kg NFM) values than nononcology patients (V 1 of 21.4 liters/57.5 kg NFM and Q of 0.84 liters/h/56.1 kg NFM).…”

Gentamicin Population Pharmacokinetics in Pediatric Patients—A Prospective Study with Data Analysis Using the saemix Package in R

“…Hartman et al [29] recently reported data from a retrospective study in which most included patients reached peak concentrations of < 8 mg/L with the Dutch dosing scheme (infusion duration and time point after infusion stop not further defined). Wang et al [30] predicted a dose of 4 mg/kg at birth to target a peak level of 10 mg/L. Their predicted dose decreased to 3 mg/kg at 2 years of age.…”