A Prospective Clinical Study Characterizing the Influence of Morbid Obesity on the Pharmacokinetics of Gentamicin: Towards Individualized Dosing in Obese Patients

Abstract

Background and objective: Gentamicin is an aminoglycoside antibiotic predominantly used in bloodstream infections. Although the prevalence of obesity is increasing dramatically, there is no consensus on how to adjust the dose in obese individuals. In this prospective clinical study, we study the pharmacokinetics of gentamicin in morbidly obese and non-obese individuals to develop a dosing algorithm that results in adequate drug exposure across body weights.

Methods: Morbidly obese subjects undergoing bariatric surgery and non-obese healthy volunteers received one intravenous dose of gentamicin (obese: 5 mg/kg based on lean body weight, non-obese: 5 mg/kg based on total body weight [TBW]) with subsequent 24-h sampling. All individuals had a normal renal function. Statistical analysis, modelling and Monte Carlo simulations were performed using R version 3.4.4 and NONMEM^® version 7.3.

Results: A two-compartment model best described the data. TBW was the best predictor for both clearance [CL = 0.089 × (TBW/70)^0.73] and central volume of distribution [V_c = 11.9 × (TBW/70)^1.25] (both p < 0.001). Simulations showed how gentamicin exposure changes across the weight range with currently used dosing algorithms and illustrated that using a nomogram based on a 'dose weight' [70 × (TBW/70)^0.73] will lead to similar exposure across the entire population.

Conclusions: In this study in morbidly obese and non-obese individuals ranging from 53 to 221 kg we identified body weight as an important determinant for both gentamicin CL and V_c. Using a body weight-based dosing algorithm, optimized exposure across the entire population can be achieved, thereby potentially improving efficacy and safety of gentamicin in the obese and morbidly obese population.

Trial registration: Registered in the Dutch Trial Registry (NTR6058).

Fig. 1

Observed gentamicin plasma concentrations (mg/L) versus time after start of infusion (h) for morbidly obese (receiving 5 mg/kg lean body weight, black lines) and non-obese (receiving 5 mg/kg total body weight, grey lines) individuals. Each line represents one individual

Fig. 2

Individual values (n = 28) for a central volume of distribution (in L) and b clearance (in L/min) versus total body weight from the base model. The black line represents the covariate relation as implemented in the final model (Table 2). CL clearance, TBW total body weight, V_c central volume of distribution

Fig. 3

Prediction-corrected visual predictive checks of the final model for non-obese (upper left panel) and obese (upper right panel) individuals. The observed concentrations are shown as black circles; the median and 2.5th and 97.5th percentiles of the observed data are shown as the solid and lower and upper dashed lines, respectively. The gray shaded areas show the 95% confidence intervals of the median (dark gray) and 2.5th and 97.5th percentiles (light gray) of the simulated concentrations (n = 1000) based on the original dataset. Lower panels show the observed proportion below the limit of quantification (black dots), where shaded areas represent the 95% confidence interval of the proportion based on the simulated concentrations (n = 1000). LOQ limit of quantification

Fig. 4

Boxplots (median and 95% confidence interval) representing gentamicin AUC₂₄ (upper panel) and C_min (lower panel) for different weight categories based on Monte Carlo simulations with six different TBW-, LBW- (calculated with the Janmahasatian formula [18]), and ABW [calculated as IBW + 0.4 × (TBW – IBW)]-based dosing regimens (n = 10,000 per regimen). The proposed nomogram is based on a ‘dose weight’ calculated as 70 × (TBW/70)^0.73 (shown in Table 3). The dashed line represents the median value of 5 mg/kg TBW in the < 100 kg group as a target reference for AUC₂₄ (upper panel) or 1 mg/L as a target reference for C_min (lower panel). ABW adjusted body weight, AUC₂₄ area under the concentration–time curve from time zero to 24 h, C_min minimum (trough) concentration, LBW lean body weight, TBW total body weight