E. AsÃn-Prieto, (1,2), A. Soraluce (1,2), A. RodrÃguez-Gascón (1,2), H. Barrasa (3), A. Isla (1,2)
(1) Pharmacokinetics, Nanotechnology and Gene Therapy Group, Faculty of Pharmacy, University of the Basque Country; Vitoria-Gasteiz, Spain. (2) Lascaray ikergunea research center, University of the Basque Country; Vitoria-Gasteiz, Spain. (3) Service of Intensive Care, University Hospital of Alava; Vitoria-Gasteiz, Spain.
Objectives: The aim of this study was to develop a population pharmacokinetic (PPK) model of daptomycin (PIP) administered to critically ill patients of the Intensive Care Unit (ICU) for the treatment of infections by Staphylococcus aureus.
Methods: Plasma concentration-time data were obtained from patients who received a dose of 350 or 500 mg of daptomycin every 24 or 48 hours (5.0 to 6.9 mg/kg) administered as a short intravenous infusion. Five blood samples were drawn from each patient and were analyzed using HPLC-UV. Demographic and laboratory data were collected including age, gender, body mass index, creatinine clearance, serum albumin or serum bilirrubin. The APACHE II score was reported for each patient. Total drug concentrations in plasma were modeled using NONMEM 7.2 and FOCE-I estimation method. Once a base model was selected, patient characteristics were explored for influence on PK parameters. The selected model was evaluated by bootstrap and visual predictive check.
Results: Ten patients were analyzed (3 men and 7 women) with an average age of 67 years (from 48 to 83 years) and creatinine clearance (CLCR) from 20 to 152 mL/min. A one-compartment model with first order elimination best fitted the data. Regarding the inclusion of characteristic of the patients in the model, the CLCR resulted in a significant covariate of the daptomycin total plasma clearance (CL), allowing to diminish the unexplained inter-individual variability (IIV) associated to the CL from 54.3% to 25.2%. However, none of the patient characteristics allowed to explain the IIV associated to the volume of distribution (Vd). The population Vd was 9.5 L with an associated IIV of 23.1% (shrinkage 28.8%). The daptomycin clearance was defined by the next equation: CL (L/h) = 0.131 + 0.0947·CLCR, with an IIV of 25.2% (shrinkage 4.1%). The proportional error resulted in a 30% (shrinkage 10.9%).
Conclusions: A one-compartment model best described the distribution of daptomycin in the patients. The creatinine clearance was a significant covariate of the daptomycin total body clearance, which is explained because the elimination of daptomycin is mainly renal. This model can be used to perform pharmacokinetic/pharmacodynamic analysis and optimize the dosing regimens based on the characteristics of the patients and the susceptibility of the microorganism involved in the infection.
Reference: PAGE 23 () Abstr 3189 [www.page-meeting.org/?abstract=3189]
Poster: Drug/Disease modeling - Infection