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

Abstract

Purpose Tobramycin 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. Methods Morbidly 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. Results In 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)). Conclusions In 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. Electronic supplementary material The online version of this article (10.1007/s11095-019-2651-2) contains supplementary material, which is available to authorized users.

Comprehensive guidance for antibiotic dosing in obese adults: 2022 update

“…An AUC‐guided aminoglycoside dosing strategy has gained momentum in the literature, but implementation is hindered by operational barriers and lack of consensus on definitive AUC/MIC efficacy targets. Several AUC‐based dosing methods in obese patients has been suggested with use of first‐order PK equations (requiring bedside calculation) or nomograms, but require validation in a real‐world clinical setting 78–80 . The current standard remains to dose aminoglycosides on a mg/kg basis using AdjBW coupled with individualized TDM 9 …”

“…79 As such, the authors proposed a novel weightbased (using TBW), CKD-EPI-based gentamicin dosing strategy for obese patients >100 kg, with a suggested 25% dose reduction in ICU patients, to approximate exposures (median AUC 0-24 of 85.9 mg•h/L) as lean patients dosed 6 mg/kg. 79 Smit et al 80 as those were the values observed in the study participants. 80 Of note, the AUC target of 75 mg•h/L is thought to maximize the probability of effect versus toxicity for pathogens with MICs between 0.5 and 1 mg/L, but higher targets are likely needed for MICs between 2 and 4 mg/L.…”

“…The authors proposed a tobramycin dosing nomogram of [Dose (mg) = AUC 24 , target × 6.33 × (1+ 0.0099 × (MDRD −115))], in which the AUC target is 75 mg∙h/L and MDRD represents the de‐indexed MDRD in mL/min. The authors caution that this nomogram is only applicable to MDRD values from 77 to 171 mL/min as those were the values observed in the study participants 80 . Of note, the AUC target of 75 mg∙h/L is thought to maximize the probability of effect versus toxicity for pathogens with MICs between 0.5 and 1 mg/L, but higher targets are likely needed for MICs between 2 and 4 mg/L 8,9 …”

“…Smit et al 80 also conducted a richly sampled PK study of 20 obese patients (median BMI 41.9 kg/m 2 ) receiving tobramycin 5 mg/kg (LBW) undergoing bariatric surgery and eight healthy volunteers and found tobramycin clearance was best predicted using a de‐indexed MDRD. The authors proposed a tobramycin dosing nomogram of [Dose (mg) = AUC 24 , target × 6.33 × (1+ 0.0099 × (MDRD −115))], in which the AUC target is 75 mg∙h/L and MDRD represents the de‐indexed MDRD in mL/min.…”

Dose recommendations for gentamicin in the real-world obese population with varying body weight and renal (dys)function

“… 28 In contrast, for other renally excreted drugs such as tobramycin and vancomycin, increased clearance values were observed with increasing body weights, albeit to varying extents and using varying covariate functions. 29 , 30 Considering the second explanation, the organic cation transporter 2 (OCT2) has been shown to be increased in obese overfed mice and obese humans, and is associated with increased renal gentamicin tubular uptake. 31 Consequently, we anticipate that the increase in gentamicin clearance with obesity may be related to the increase in OCT2 transporters in the kidneys of obese individuals.…”