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

Abstract

The aminoglycoside gentamicin is used for the empirical treatment of pediatric infections. It has a narrow therapeutic window. In this prospective study at University Children’s Hospital Zurich, Switzerland, we aimed to characterize the pharmacokinetics of gentamicin in pediatric patients and predict plasma concentrations at typical recommended doses. We recruited 109 patients aged from 1 day to 14 years, receiving gentamicin (7.5 mg/kg at age ≥ 7 d or 5 mg/kg). Plasma levels were determined 30 min, 4 h and 24 h after the infusion was stopped and then transferred, together with patient data, to the secure BioMedIT node Leonhard Med. Population pharmacokinetic modeling was performed with the open-source R package saemix on the SwissPKcdw platform in Leonhard Med. Data followed a two-compartment model. Bodyweight, plasma creatinine and urea were identified as covariates for clearance, with bodyweight as a covariate for central and peripheral volumes of distribution. Simulations with 7.5 mg/kg revealed a 95% CI of 13.0–21.2 mg/L plasma concentration at 30 min after the stopping of a 30-min infusion. At 24 h, 95% of simulated plasma levels were < 1.8 mg/L. Our study revealed that the recommended dosing is appropriate. It showed that population pharmacokinetic modeling using R provides high flexibility in a secure environment.

Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology – application to amikacin

“…In general, many different exposure questions can be addressed, but clinical limitations with respect to formulated targets need to be kept in mind for final dosing decisions, as illustrated in figure 1 by expert opinion relevance (e.g., in our case uncertainty concerning the actual risk of oto-/nephrotoxicity associated with short-term high C trough , an optimal C trough cutoff to define "elevated" C trough values under varying dosing intervals, and duration of post-antibiotic effect [48][49][50]). Simulations may be easily adjusted and updated if new evidence emerges regarding exposure targets, such as increasing minimal inhibitory concentration (MIC), as has been observed for gentamicin [12,51]. Improved infrastructures allowing the collection and use of real-world data for scientific purposes [52] will further facilitate the development and evaluation of such model-informed dosing approaches and their implementation in a learn-and-confirm cycle (figure 1).…”

SwissPKcdw – A clinical data warehouse for the optimization of pediatric dosing regimens

“…The timespan in which the patients were treated with the drug and data has been logged is, on average, 200 days, whereas the longest registered timespan is 1414 days. The gentamicin routine dataset is the largest in terms of number of patients (266) 39 whereas they were, on average, 2 years old at the time of treatment. The data set of a prospective pharmacokinetic study comprises 126 patients which were treated with three doses on average for a duration of 7 days in total.…”