Population pharmacokinetics of imipenem bone concentrations in pigs
A.-L. FLAUGERE(1), M. CARLES(2), E. RAMAIN (2), A. BOULAMERY-VELLY(1), N. SIMON(1)
(1)Laboratoire de pharmacologie médicale et clinique, AP-HM, Université de la méditerranée, Marseille, France, (2)Département d'anesthésiologie, Nice, France
Objectives: Imipenem (IPM) is a broad-spectrum β-lactam antibiotic frequently used in intensive care units to treat nosocomial infections and BGN infections. It allows to treat severe infections of all body systems notably bone infections. The objective of the present study was to investigate the bone distribution of IPM by microdialysis in healthy pigs.
Methods: Eight healthy pigs (26-30kg) were included. They were anesthetized and an arterial catheter and a medullar bone microdialysis probe were inserted in the left posterior tibia. Then, pigs received an intravenous infusion of 15mg.kg-1 of IPM over a 30-min period. Blood samples and bone dialysates were collected at 5, 15, 30, 45, 60, 120, 180, 240 and 300 min following infusion. Determination of IPM concentrations in plasma and microdialysat were determined by a validated HPLC method with UV-VIS detection (Dionex detector UVD170U). The in vivo recovery of the microdialysis was evaluated by retrodialysis (63%). Data were analysed using the non linear mixed effect modeling software program nonmem (version VI.2). Plasma and bone concentrations were described using the nonmem subroutines ADVAN3 and ADVAN6.
Results: A 3-compartments model was used to describe the whole dataset, 2 compartments for the plasma concentrations and 1 compartment for bone concentrations. The PK parameters were the following : total clearance CL 7.08 L/h (se 13%), volume of distribution of the central compartment V1 2.56 L (se 8%), intercompartmental clearance Q 3.43 L/h (se 18%), volume of distribution of the peripheral compartment V2 2.59 L (se 9.9%), the first order intercompartment rate constant from central to bone compartment (K13) 0.21 L/h (se 45%) and the first order intercompartment rate constant from bone to the central compartment (K31) 2.46 L/h (se 23%). The InterIndividual Variability was evaluated only on CL (22%, se 44%) and K13 (61%, se 25%). Two residual errors were used, one for plasma (22%, se 33%) and one for bone data (37%, se 43%). The model was validated using a bootstrap analysis and goodness of fit plots with normalized predictive distribution error.
Conclusions: The estimation of total clearance (0.25 L/h/kg) and volume of distribution (0.17 L/kg) in pigs are in agreement with those obtained in human (0.2 L/h/kg and 0.2-0.3 L/kg). These results suggest that pig is a useful model for evaluation of IPM PK. Our 3-compartment model which includes bone allows extrapolating bone concentrations in human.
