Cornelis Smit (1,2), Anne M. van Schip (3,4,5), Eric P.A. Van Dongen (6), Roger J.M. Brüggemann (7), Matthijs L. Becker (3,4), Catherijne A.J. Knibbe (1,2)
(1) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands (2) Department of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (3) Pharmacy Foundation of Haarlem Hospitals, Haarlem, The Netherlands (4) Department of Hospital Pharmacy, Spaarne Gasthuis, Haarlem, The Netherlands (5) Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands. (6) Department of Anesthesiology, St. Antonius Hospital, Nieuwegein, The Netherlands (7) Department of Pharmacy, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, The Netherlands
Objectives The impact of weight on pharmacokinetics of gentamicin, an aminoglycoside antibiotic predominantly used in severe infections, was recently quantified across non obese and morbidly obese individuals with normal renal function, upon which a weight-based dose nomogram was proposed [1]. Since both renal function and (critical) illness are known to influence gentamicin clearance, [2] it is likely that an adaptation of this dose nomogram is required for the real-world obese patients with a varying degree of renal function. The current study aims to characterize the pharmacokinetics of gentamicin in real-world obese patients, ultimately to develop dose recommendations that are applicable across the entire obese population.
Methods Data from a prospective rich full PK study on 28 non-obese and morbidly obese with normal renal function [1] were combined with therapeutic drug monitoring data from two large Dutch hospitals. For the hospital data sets, all admitted patients with BMI ≥25 kg/m2 with ≥1 gentamicin administration, ≥1 gentamicin and creatinine serum concentration measurement were included. Data on gentamicin administrations, dosages, concentrations and potentially relevant covariates such as body weight descriptors (total body weight (TBW), lean body weight (LBW), adjusted body weight (ABW), body surface area (BSA)), serum creatinine based renal function estimates (MDRD, CKD-EPI or CG calculated with either LBW or TBW), age, gender and stay at an ICU were obtained from the electronic health record system. De-indexed values for MDRD and CKD-EPI (in ml/min) were obtained by multiplying with BSA/1.73. Data from the rich prospective data of 28 non-obese and morbidly obese with normal renal function [1] combined with the data from one hospital, served as the training dataset. Data from the second hospital served as external validation dataset. Population pharmacokinetic modeling was performed using NONMEM v7.4.3 [3]. 95% confidence intervals of parameters were assessed by the sampling importance resampling (SIR) [4].
Monte Carlo simulations of a single gentamicin administration with different dose strategies were performed in subjects with randomly assigned CKD-EPI and TBW values (n=10.000). For ABW-based dose strategies, realistic combinations of weight, height and gender were obtained by resampling combinations from the NHANES database [5]. The median AUC0-24 from a reference subset of lean (non-ICU) subjects with a TBW 60 ml/min/1.73 m2 receiving 6 mg/kg TBW was used as a target (currently recommended standard dose by EUCAST [6]).
Results The training dataset (1187 observations from 542 individuals with TBW 52–221 kg and CKD-EPI 5.1–141.7 ml/min/1.73 m2) showed that in a two-compartment model, clearance was best predicted using de-indexed CKD-EPI and ICU-stay (both p<0.001, value [95% CI]: CL (L)=3.53 [3.36–3.71] x (de-indexed CKD-EPI)/78) x 0.75 [0.67–0.84] (if ICU), where V1 was best predicted by TBW (p<0.001): V1= 16.6 [15.1–18.1] x TBW/70. The model was confirmed using the independent validation dataset (321 observations from 208 individuals, TBW 67–180 kg, CKD-EPI 5.2–130.0 ml/min/1.73 m2), based on MPE (-0.39 mg/L, 95% CI -8.98 – 1.70 mg/L) goodness-of-fit and pvcVPC.
A CKD-EPI based dose regimen was designed for obese individuals with varying renal (dys)function consisting of body weight (i.e. mg/kg dosing) and indexed CKD-EPI (ml/min/1.73 m2). Proposed dosages range from 1.8 mg/kg (CKD-EPI 120 ml/min), with extension of dosing intervals from 24 to 48h when CKD-EPI drops below 50 ml/min. Using this dose recommendation, similar exposures with similar variability over the first 24-hours after infusion are obtained compared to lean individuals without renal impairment receiving the standard dose of 6 mg/kg TBW [6]. TBW- and ABW-based dose regimens (mg/kg) will yield unacceptably high exposures with decreasing CKD-EPI.
Conclusions We successfully characterized and externally validated the pharmacokinetics of gentamicin in clinical (morbidly) obese individuals with varying renal (dys)function. We propose specific mg/kg dose reductions with decreasing CKD-EPI values for the obese population, and extension of the dosing interval beyond 24h when CKD-EPI drops below 50 ml/min. In ICU patients, a 25% dose reduction could be considered. These guidelines can be used to guide safe and effective dosing of gentamicin across the real world obese population.
References:
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[8] European Committee on Antimicrobial Susceptibility Testing (EUCAST). Clinical breakpoints – bacteria (v 10.0). 2020.
Reference: PAGE () Abstr 9283 [www.page-meeting.org/?abstract=9283]
Poster: Oral: Drug/Disease Modelling