Population pharmacokinetics of vancomycin in obesity: Finding the optimal dose for (morbidly) obese individuals

Aims: For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (area under the curve 400-700 mg h L^-1 ). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and nonobese individuals, in order to guide vancomycin dosing in the obese.

Methods: Morbidly obese individuals (n = 20) undergoing bariatric surgery and nonobese healthy volunteers (n = 8; total body weight [TBW] 60.0-234.6 kg) received a single vancomycin dose (obese: 12.5 mg kg^-1 , maximum 2500 mg; nonobese: 1000 mg) with plasma concentrations measured over 48 h (11-13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n = 10.000 individuals, TBW 60-230 kg) were performed using NONMEM.

Results: In a 3-compartment model, peripheral volume of distribution and clearance increased with TBW (both p < 0.001), which was confirmed in the external validation. A dose of 35 mg kg^-1 day^-1 (maximum 5500 mg/day) resulted in a > 90% target attainment (area under the curve > 400 mg h L^-1 ) in individuals up to 200 kg, with corresponding trough concentrations of 5.7-14.6 mg L^-1 (twice daily dosing). For continuous infusion, a loading dose of 1500 mg is required for steady state on day 1.

Conclusion: In this prospective, rich sampling pharmacokinetic study, vancomycin clearance was well predicted using TBW. We recommend that in obese individuals without renal impairment, vancomycin should be dosed as 35 mg kg^-1 day^-1 (maximized at 5500 mg/day). When given over 2 daily doses, trough concentrations of 5.7-14.6 mg L^-1 correspond to the target exposure in obese individuals.