AsÃn E (1), Trocóniz IF (2), Campos E (3), Errasti J (3), Sáenz de Ugarte J (3), Gascón AR (1), Isla A (1)
(1) Pharmacokinetics, Nanotechnology and Gene Therapy Group, Faculty of Pharmacy, University of the Basque Country; Vitoria-Gasteiz, Spain. (2) Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra; (3) Service of General Surgery, University Hospital of Alava (seat of Txagorritxu); Vitoria-Gasteiz, Spain.
Objectives: The aim of this study is to develop a population pharmacokinetic model for cefuroxime used as prophylaxis in patients undergoing colorectal surgery in order to quantify the degree of inter-individual variability (IIV) and identify the patient and surgery characteristics responsible for such variability.
Methods: A prospective, open-label study was conducted with patients electively undergoing colorectal surgery. The study was conducted at University Hospital of Alava (seat of Txagorritxu) in Vitoria, Spain. Sixty-four patients older than 18 years were included in the study. According to the surgical protocol of the Hospital, all patients received 1.5 g of cefuroxime concomitantly with 1.5 g of metronidazole as intravenous infusion previously to the surgery. A predose blood sample and three to five samples during the next 24 h were collected from each patient. Determination of cefuroxime plasma concentrations was carried out by HPLC. A population pharmacokinetic model was developed using NONMEM 7.2 and the FOCE estimation method with interaction. Compartmental models were used to fit the data. Selection between models was based on the decrease of the objective function value, the precision of parameter estimates and the goodness of fit plots.
Results: Seventeen surgery and patients characteristics were studied as covariates in order to explain the IIV for the parameters. Cefuroxime concentrations were best described by a two-compartment model. IIV was included in the total body clearance (CL) and the apparent volume of distribution of the central compartment (Vc). Cefuroxime is eliminated renally by a one-order process (glomerular filtration) dependent directly on the creatinine clearance and a saturable process (active secretion) which is dependent on the concentration achieved. The body weight and the ASA score were significant covariates for the Vc. The inclusion of covariates allowed to reduce the unexplained IIV from 37% to 17% for the CL, and from 56% to 40% for the Vc.
Conclusions: A two-compartment pharmacokinetic model for cefuroxime in patients submitted to colorectal surgery was developed. The inclusion of covariates reduced significantly the unexplained IIV of the pharmacokinetic parameters. This model could be useful to study whether antibiotic concentration is able to inhibit the bacteria growth until the wound closing time, and to establish recommendations to reduce the incidence of infection in this type of surgery.
Reference: PAGE 22 (2013) Abstr 2919 [www.page-meeting.org/?abstract=2919]
Poster: Infection