DDMODEL00000315: PK_Gentamicin_Obese

  public model
Short description:
PK model for gentamicin in non-obese and obese individuals with normal renal function
Original code
  • A Prospective Clinical Study Characterizing the Influence of Morbid Obesity on the Pharmacokinetics of Gentamicin: Towards Individualized Dosing in Obese Patients.
  • Smit C, Wasmann RE, Goulooze SC, Hazebroek EJ, Van Dongen EPA, Burgers DMT, Mouton JW, Brüggemann RJM, Knibbe CAJ
  • Clinical pharmacokinetics, 10/2019, Volume 58, Issue 10, pages: 1333-1343
  • Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.
  • 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 identified body weight as an important determinant for both gentamicin CL and Vc. 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).
Cornelis Smit
Context of model development: Patient Population Selection and Bridging between Population (Pediatrics, Elderly, Obese);
Long technical model description: A 2-compartment model with combined error model and M3 method for BLQ data with weight as covariate on CL and V1;;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Dose finding for the obese population;
Modelling task in scope: simulation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: Anti-infectives;
Annotations are correct.
This model is not certified.
  • Model owner: Cornelis Smit
  • Submitted: Jan 31, 2020 5:41:00 PM
  • Last Modified: Jan 31, 2020 5:41:00 PM
  • Version: 9 public model Download this version
    • Submitted on: Jan 31, 2020 5:41:00 PM
    • Submitted by: Cornelis Smit
    • With comment: Updated model annotations.