Margreke JE Brill(1,5), Aletta PI Houwink(2), Stephan Schmidt(3), Eric J Hazebroek(4), Bert van Ramshorst(4), Eric PA van Dongen(3), Catherijne AJ Knibbe(1,5)
(1) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands; (2) Department of Anaesthesiology and Intensive Care, St. Antonius Hospital, Nieuwegein, The Netherlands; (3) Center for Pharmacometrics & System Pharmacology, Department of Pharmaceutics, University of Florida, U.S.A. (4) Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands; (5) Division of Pharmacology, Leiden/ Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands
Objectives: Morbidly obese patients are prone to surgical site infections. To reduce the risk of infection a prophylactic antibiotic agent is administered before initial surgical incision to attain adequate levels of antibiotic in the bloodstream and subcutaneous tissues. For gastric surgery, cefazolin is the prophylactic antibiotic agent of choice. Currently it is unknown how morbid obesity affects cefazolin pharmacokinetics. In this study, we aimed to investigate the pharmacokinetics of cefazolin, in particular regarding protein binding and subcutaneous adipose tissue distribution in morbidly obese patients and non-obese patients.
Methods: Eight morbidly obese patients, of which seven were eligible for inclusion, with a mean body mass index (BMI) of 48 ± 6 kg/m2 (range 41 – 57 kg/m2) and seven non-obese patients with a mean BMI of 28 ± 3 kg/m2 (range 24 – 31 kg/m2) received cefazolin 2 gram i.v. at the induction of anesthesia. Total cefazolin serum concentrations were measured at T= 10, 30 and 240 minutes. Unbound serum concentrations were measured at T=0, 5, 10, 30, 60, 120 and 240 min. Using microdialysis, samples to measure unbound cefazolin concentrations in subcutaneous adipose tissue of the abdomen were collected every 20 minutes until 240 minutes after dosing. Population pharmacokinetic modeling and covariate analysis characterizing the influence of body weight and other covariates was performed using NONMEM VI.
Results: A two compartment model consisting of a one compartment model with saturable protein binding (maximal bound concentration Bmax of 215 (6%) mg/L and KD of 73 (10%) microM) for total and unbound cefazolin in serum and a one compartment model for unbound cefazolin in subcutaneous adipose tissue best described the data. Distribution from the central to subcutaneous compartment was dependent on total body weight. Total body weight was a covariate for central volume of distribution (P<0.01) while there was no influence of total body weight on cefazolin protein binding parameters.
Conclusions: A population pharmacokinetic model for cefazolin in morbidly obese and non obese patients was derived with a saturable protein binding model for cefazolin in serum and a body weight dependent distribution to the subcutaneous adipose tissue.
Reference: PAGE 22 () Abstr 2882 [www.page-meeting.org/?abstract=2882]
Poster: Infection