Retrieving the Optimal Gentamicin Dose for (Morbidly) Obese Patients: A Prospective Clinical Study

Abstract

Background: Gentamicin is an aminoglycoside antibiotic predominantly used in bloodstream infections. While the prevalence of obesity is increasing dramatically, there is no consensus on how to adjust the dose in these individuals, for which adjusted body weight (ABW) or, more recently, lean body weight (LBW) have been proposed. In this prospective clinical study, we study the pharmacokinetics of gentamicin in obese and non-obese individuals to develop a dosing algorithm that results in adequate drug exposure across the whole clinical population. Methods: Morbidly obese subjects undergoing bariatric surgery and non-obese healthy volunteers received one IV dose of gentamicin (obese: 5 mg/kg LBW, non-obese: 5 mg/kg total body weight) over 30 minutes with subsequent 24 hour sampling. Statistical analysis, modelling and Monte Carlo simulations were performed using R 3·4·3 and NONMEM 7·3. Findings: In morbidly obese individuals (n = 20, 109-221 kg) dosed on LBW, both AUC0-24h and Cmax were lower compared to non-obese individuals (n = 8, 53-86 kg) dosed on total body weight (mean difference (95% CI): -25·0 mg/L*h (-16·7 - -33·3 mg/l*h) and -8·7 mg/L, (-6·5 - -11·0 mg/L), respectively). Body weight was the best predictor for both clearance and central volume of distribution (P< 0·001, P < 0·001). Simulations show that dosing based on an allometric dose weight (70 x (TBW/70)0·73) will lead to similar exposure across the entire population. Clincial Trial Number: The study was registered in the Dutch Trial Registry (NTR6058) Funding Statement: ZonMW (grant 836041004). Declaration of Interests: R.J.M. Bruggemann declares that he has no conflicts of interest with regards to this work. Outside of this work, he has served as consultant to and has received unrestricted research grants from Astellas Pharma Inc., F2G, Gilead Sciences, Merck Sharpe and Dohme Corp., and Pfizer Inc. All payments were invoiced by the Radboud University Medical Center. Other authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Ethics Approval Statement: The study was approved by the local human research and ethics committee and was conducted in accordance with the principles of the Declaration of Helsinki.