Estimation of population pharmacokinetics parameters of amikacin in pediatric cystic fibrosis patients using a nonlinear mixed effects method.

CACERES GUIDO P; PEREZ M; HALAC A; FERRARI M; LICCIARDONE N; BRAMUGLIA G; CASTAÑOS; MATO G; P. SCHAIQUEVICH

Stuttgart

Congreso; 12 th international congress of therapeutic drug monitoring and clinical toxicology; 2011

Background: amikacin (AMK) is an aminoglycoside antibiotic used in the treatment of chronic lung infection by Pseudomonas aeruginosa in pediatric cystic fibrosis (CF) patients. The aim of the present study was to characterize AMK pharmacokinetics (PK) and the intra-individual (residual) variability using a population approach. Methods: prospective analysis carried out in CF pediatric patients at Garrahan Pediatric´s Hospital between May 2004 and July 2009. Patients: n = 54; age ± SD: 6.6 ± 5.2 years. AMK dosages: 15 to 30 mg/kg/day (Q8, Q12 or Q24 hs). A total of 148 AMK plasma levels were determined by polarized immunofluorescence, in general immediately before and half an hour after the end of the infusion for each patient. PK population parameters were estimated using nonlinear mixed effects modeling method (Monolix 3.2). The structural model was built considering a one-compartment model. The residual variability was modeled using a proportional error model, which was chosen on the basis of graphical and analytical criteria. Results: The population pharmacokinetic parameters obtained for the structural model were clearance (CL): 3.23 L/h and volume of distribution (V): 9.39 L.  The relative standard error was 8% for both V and CL. Omega V was 0.413 (21%) and Omega CL was 0.616 (13%).Conclusions: for the first time AMK population PK was characterized in CF pediatric patients using Monolix. Based on these results we suggest that well designed clinical trials, which correlate PK and pharmacodynamics parameters, are needed re-define new useful and safe therapeutic ranges in the studied population.