Amikacin initial dosage in patients with hypoalbuminaemia: an interactive tool based on a population pharmacokinetic approach.

Abstract

To characterize amikacin population pharmacokinetics in patients with hypoalbuminaemia and to develop a model-based interactive application for amikacin initial dosage. A population pharmacokinetic model was developed using a non-linear mixed-effects modelling approach (NONMEM) with amikacin concentration-time data collected from clinical practice (75% hypoalbuminaemic patients). Goodness-of-fit plots, minimum objective function value, prediction-corrected visual predictive check, bootstrapping, precision and bias of parameter estimates were used for model evaluation. An interactive model-based simulation tool was developed in R (Shiny and R Markdown). Cmax/MIC ratio, time above MIC and AUC/MIC were used for optimizing amikacin initial dose recommendation. Probabilities of reaching targets were calculated for the dosage proposed. A one-compartment model with first-order linear elimination best described the 873 amikacin plasma concentrations available from 294 subjects (model development and external validation groups). Estimated amikacin population pharmacokinetic parameters were CL (L/h) = 0.525 + 4.78 × (CKD-EPI/98) × (0.77 × vancomycin) and V (L) = 26.3 × (albumin/2.9)-0.51 × [1 + 0.006 × (weight - 70)], where CKD-EPI is calculated with the Chronic Kidney Disease Epidemiology Collaboration equation. AMKdose is a useful interactive model-based application for a priori optimization of amikacin dosage, using individual patient and microbiological information together with predefined pharmacokinetic/pharmacodynamic (PKPD) targets. Serum albumin, total bodyweight, estimated glomerular filtration rate (using the CKD-EPI equation) and co-medication with vancomycin showed a significant impact on amikacin pharmacokinetics. A powerful interactive initial dose-finding tool has been developed and is freely available online. AMKdose could be useful for guiding initial amikacin dose selection before any individual pharmacokinetic information is available.