Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Non-obese Individuals: Results of a Prospective Rich Sampling Pharmacokinetic Study

Cornelis Smit,Catherijne A. J. Knibbe,Roger J. M. Brüggemann,Marinus J. Wiezer,Hendricus P. A. van Dongen,Johan W. Mouton,Roeland E. Wasmann

doi:10.1007/s11095-019-2651-2

Abstract

PurposeTobramycin is an aminoglycoside antibiotic of which the 24 h exposure correlates with efficacy. Recently, we found that clearance of the aminoglycoside gentamicin correlates with total body weight (TBW). In this study, we investigate the full pharmacokinetic profile of tobramycin in obese and non-obese individuals with normal renal function.MethodsMorbidly obese individuals (n = 20) undergoing bariatric surgery and non-obese healthy volunteers (n = 8), with TBW ranging 57–194 kg, received an IV dose of tobramycin with plasma concentrations measured over 24 h (n = 10 per individual). Statistical analysis, modelling and simulations were performed using NONMEM.ResultsIn a two-compartment model, TBW was the best predictor for central volume of distribution (p < 0.001). For clearance, MDRD (de-indexed for body surface area) was identified as best covariate (p < 0.001), and was superior over TBW ((p < 0.05). Other renal function estimates (24 h urine GFR and de-indexed CKD-EPI) led to similar results as MDRD (all p < 0.001)).ConclusionsIn obese and non-obese individuals with normal renal function, renal function estimates such as MDRD were identified as best predictors for tobramycin clearance, which may imply that other processes are involved in clearance of tobramycin versus gentamicin. To ensure similar exposure across body weights, we propose a MDRD-based dosing nomogram for obese patients.

Highlights

The global prevalence of obesity and morbid obesity, which is commonly defined as a body mass index (BMI) over 30 and 40 kg/m2, respectively, is rapidly rising
In the current prospective rich sampling study, we investigate the pharmacokinetics of tobramycin in morbidly obese and non-obese individuals with normal renal function, in order to investigate how tobramycin clearance and other PK parameters change in obesity
The AUC24 was significantly lower in the obese group receiving tobramycin as a single 5 mg/kg lean body weight (LBW) dose compared to the non-obese control group receiving a 5 mg/kg total body weight (TBW) dose

Summary

Introduction

The global prevalence of obesity and morbid obesity, which is commonly defined as a body mass index (BMI) over 30 and 40 kg/m2, respectively, is rapidly rising. The exact quantification of these changes in PK and PD is lacking for many drugs This is of particular relevance for drugs for which a target concentration and/or exposure related to efficacy or safety has been identified, like in the case of aminoglycosides. Since in the general population AUC24 closely correlates with the maximum plasma concentration (Cmax) and measurement of an AUC puts substantial burden to the treated patient, the Cmax is often used as measure of efficacy with target values between 15 and 20 mg/L Despite this approach that is used in clinical practice, the AUC24 is still considered the cornerstone PD-index for aminoglycoside effectivity and toxicity [5,6,7], with 75 mg*h/L being proposed as a pharmacodynamic target with an optimal effect and acceptable risk for toxicity [5]. This is based on the assumption that MICs are not higher than 1 mg/L, whereas the wild-type population of most gramnegatives extend to 2 mg/L [5,8]

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