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

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 [Vc = 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 identifed body weight as an important determinant for both gentamicin CL and Vc. Using a body weight-based dosing algorithm, optimized exposure across the entire p

Quantifying Beta‐Galactosylceramide Kinetics in Cerebrospinal Fluid of Healthy Subjects Using Deuterium Labeling

Therapeutics promoting myelin synthesis may enhance recovery in demyelinating diseases, such as multiple sclerosis. However, no suitable method exists to quantify myelination. The turnover of galactosylceramide (myelin component) is indicative of myelination in mice, but its turnover has not been determined in humans. Here, six healthy subjects consumed 120 mL 70% D(2)O daily for 70 days to label galactosylceramide. We then used mass spectrometry and compartmental modeling to quantify the turnover rate of galactosylceramide in cerebrospinal fluid. Maximum deuterium enrichment of body water ranged from 1.5–3.9%, whereas that of galactosylceramide was much lower: 0.05–0.14%. This suggests a slow turnover rate, which was confirmed by the model‐estimated galactosylceramide turnover rate of 0.00168 day(−1), which corresponds to a half‐life of 413 days. Additional studies in patients with multiple sclerosis are needed to investigate whether galactosylceramide turnover could be used as an outcome measure in clinical trials with remyelination therapies