C. Couffignal (1,5), O. Pajot (2), L. Massias (3), A. Foucrier (4) , C. Laouénan (1,5), M. Wolff (4) and F. Mentré (1,5)
(1) AP-HP, Hop Bichat, Biostatistic Dept, Paris, France, (2) Hop V Dupouy, Intensive Care Unit, Argenteuil, France, (3) AP-HP, Hop Bichat, Pharmacy Dept, Paris, France, (4) AP-HP, Hop Bichat, Intensive Care Unit, Paris, France, (5) Univ Paris Diderot, Sorbonne Paris Cité and INSERM, UMR 738, Paris, France
Objectives: Imipenem is often used for empirical treatment of ventilated-associated pneumonia (VAP). Large interindividual variations in the pharmacokinetic parameters (PK) in intensive care unit (ICU) patients have been reported [1]. The aim of our study was to determine more accurately population pharmacokinetics (PopPK) parameters of imipenem in ICU patients and the impact of covariates.
Methods: Prospective study conducted in ICU patients with presumptive diagnosis of gram-negative bacilli VAP. Imipenem was administrated every 8 h as an infusion over 0.5 h (500 to 1000 mg). Blood samples were collected at 0, 0.5, 1, 2, 5 and 8 h after the 4th dose. Imipenem plasma concentrations [C] were measured by HPLC (LOQ 0.5 mg/L). PopPK parameters were estimated by nonlinear mixed effects models using SAEM algorithm in MONOLIX 4 [2]. Influence of covariates (age, gender, weight, creatinin clairance (CrCL), serum albumin, edema score, SOFA, SAPS II, shock, PEEP, PaO2/FiO2) on PK parameters was determined using Spearman or Wilcoxon tests.
Results: 51 patients (41 males), median (range) age 60 yr (28-84) were included. Imipenem [C] at peak (0.5h) and trough were 34.1 mg/L (12.3-67.5) and 1.9 mg/L (0.5-10.1), respectively. Imipenem PK was best described by a two-compartment model. The mean and between-patient variability (%) for clearance CL and central volume of distribution VD were 12.7 L/h (43%) and 16.3 L (45%), respectively. CL was found to increase significantly with CrCL and decrease with age, SOFA and SAPS II. VD was found significantly to increase significantly with weight and edema score.
Conclusions: There is a wide variability of imipenem PK parameters in ICU patients with VAP that could lead to suboptimal antibiotic exposure in some pts. Our findings are in accordance with previous studies and we identified covariates that may explain variability of PopPK parameters [3;4].
References:
[1] Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet, 2005; 44, 1009-1034.
[2] Kuhn E, Lavielle M. Maximum likelihood estimation in nonlinear mixed effects models. Comput Stat Data Anal, 2005; 49:1020-1038.
[3] Novelli A and al. Pharmacokinetic evaluation of meropenem and imipenem in critically ill patients with sepsis. Clin Pharmacokinet, 2005; 44, 539-549.
[4] Sakka S.G and al. Population Pharmacokinetics and Pharmacodynamics of Continuous versus Short-Term Infusion of Imipenem-Cilastatin in Critically Ill Patients in a Randomized, Controlled Trial. Antimicrobial Agents and Chemotherapy, 2007;51, 3304-3310.
Reference: PAGE 22 () Abstr 2747 [www.page-meeting.org/?abstract=2747]
Poster: Infection