TY - JOUR
T1 - Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Non-obese Individuals
T2 - Results of a Prospective Rich Sampling Pharmacokinetic Study
AU - Smit, Cornelis
AU - Wasmann, Roeland E.
AU - Wiezer, Marinus J.
AU - van Dongen, Hendricus P.A.
AU - Mouton, Johan W.
AU - Brüggemann, Roger J.M.
AU - Knibbe, Catherijne A.J.
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
KW - aminoglycosides
KW - morbid obesity
KW - pharmacokinetics
KW - tobramycin
UR - http://www.scopus.com/inward/record.url?scp=85066401654&partnerID=8YFLogxK
U2 - 10.1007/s11095-019-2651-2
DO - 10.1007/s11095-019-2651-2
M3 - Article
C2 - 31147853
AN - SCOPUS:85066401654
SN - 0724-8741
VL - 36
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 8
M1 - 112
ER -