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Validation Of An Amikacin Population Pharmacokinetics Model To Be Used In Intensive Care Unit

Rizo-Manika M, Saivin S, Georges B, Conil JM, Lavit M, Houin G

Introduction: Amikacin (AMIK) is one of the most useful aminoglycoside in the treatment of severe G-negative infections. Intensive care unit’s (ICU) patients present a large pharmacokinetic variability. The aim of our study was to provide a validated pharmacokinetic model of AMIK in ICU patients by using sparse data collected during routine clinical care.

Materials and Methods: AMIK was administered intravenously over 0.5 h at once daily dosing regimens. A mixed-effect modelling (NONMEM) approach was used to fit the data. At first, the pharmacokinetics of AMIK was studied in 59 patients (201 serum concentrations). Demographics, clinical and biological covariates were tested for evaluating their influence : age, gender, weight, height, fever, general pathology, creatininemia, creatinine clearance, protidemia, uremia, leukocytes, hemoglobinemia, CRP, PLA2, simplified acute physiology scores (SAPS I et II). Concomitant medications were also studied : furosemide, vancomycin, corticosteroids, non-steroidal anti-inflammatory drugs and catecholamines. A second group of 23 patients (92 serum concentrations) was used for the validation.

Results: An open two-compartment PK model with zero-order input was used to describe the kinetics of AMIK. The statistical model chosen to describe the inter-individual variability (IIV) in pharmacokinetic parameters and the residual error was a proportional one. This model was used to predict serum AMIK concentrations in the validation group which did not differ from the model population. To determine the predictive performance of our model we have compared the mean ± SD observed (18,2 ± 19,9 mg/L) and predicted values (18,8 ± 20,0 mg/L) by computing bias (0,618; IC: -1,338 ; 2,574), precision (9,54 mg/L), average fold error (1,63) and correlation (r=0,8850). The final population model was : TVCL = (1 + 0.029 x CLCR) x (1 – 0.0154 x IGS1); TVV1 = 0.294 x WT; TVQ = 5.52; IF(PLA2.GT.10) TVQ = 2.59; TVV2 = (1.23 x CLCR) x (1 – 0.0347 x IGS1) The mean population parameters and their IIV (CV %) obtained for the 82 patients are as follows : clearance (3 L/h, 28%), initial volume of distribution (22 L, 18 %), inter-compartmental clearance (4.3 L/h, 73 %) and peripheral volume of distribution (66 L, 59 %).

Discussion-Conclusion: The mean values obtained for AMIK pharmacokinetic parameters are consistent with reported values in ICU patients. The covariates included in the model explain a part of the IIV in the pharmacokinetic parameters. Our model will permit to adjust AMIK dosage regimen in clinical routine.