Asín E (1), Trocóniz IF (2), Gascón AR (1), Arzuaga A (1), Maynar J (3), Sánchez-Izquierdo JA (4), Isla A (1)
(1) Laboratory of Pharmacy and Pharmaceutical Technology, 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) Intensive Care Unit, Hospital Universitario de Álava, Vitoria-Gasteiz, Spain; (4) Intensive Care Unit, Doce de Octubre Hospital, Madrid, Spain.
Objective: The aim of this study was to develop a population pharmacokinetic (PPK) model of piperacillin (PIP) administered to patients of the Intensive Care Unit (ICU) undergoing continuous venovenous hemofiltration.
Methods: Plasma concentration-time data were obtained from 16 patients who received piperacillin/tazobactam (4 g/0.5 g) every 4, 6 or 8 hours. Blood and ultrafiltrate samples were drawn at 0, 0.3, 0.5, 0.75, 1, 3, 4, 6 and 8 hours after dosing and were analyzed using HPLC-UV. Piperacillin plasma concentrations were modelled using NONMEM VI. Disposition of the total drug plasma concentration was modelled using compartmental models. Once a base model was selected, patient characteristics including demographic, clinical, and laboratory were explored for influence on PK parameters. Age, body weight, ultrafiltrate flow, creatinine clearance, the unbound drug fraction in plasma, proteinemia, albuminemia and serum bilirubin, were continuous covariates evaluated for significance. Sex, SOFA score (Sepsis-related Organ Failure Assessment), APACHE II score and diagnosis of sepsis were the categorical covariates studied. The sieving coefficient, defined as the fraction of the drug eliminated across the membrane during CRRT, was calculated as the ratio of area under the ultrafiltrate concentration curve to area under the serum concentration curve.
Results: Sixteen critically ill patients with a median age of 57 (range 18-77) were enrolled in the study. Piperacillin plasma concentrations were best described by a two-compartment model. The data supported the inclusion of IIV in total plasma clearance and the apparent volume of distribution. Total body clearance included a non-renal, a renal and an extracorporeal component.
Conclusions: A two-compartment pharmacokinetic model for piperacillin in patients undergoing continuous renal replacement therapies was developed. Considering that the main objective of antimicrobial treatment is to maintain free-drug plasma concentration above the MIC of the infecting pathogen, this model could be used to determine the probability of PKPD target attainment and to estimate appropriate piperacillin/tazobactam dosage guidelines in these patients.
Reference: PAGE 21 (2012) Abstr 2526 [www.page-meeting.org/?abstract=2526]
Poster: Infection