2017 - Budapest - Hungary

PAGE 2017: Drug/Disease modelling - Infection
Eirini Tsotsou

Population pharmacokinetics of gentamycin in hospitalized ICU patients

Eirini Tsotsou (1), Despoina Danassi (2), Eleni Magira (2), Spyros Zakynthinos (2), Georgia Valsami (1), Aristides Dokoumetzidis (1)

(1) Department of Pharmacy, University of Athens, Greece. (2) Evangelismos Athens General Hospital, Greece.

Objectives: To develop a PopPK model of gentamycin in ICU patients with either obesity, sepsis or acute respiratory distress syndrome, while some undergoing hemofiltration. Gentamycin is a well studied hydrophilic antibiotic, thus in these special situations the pharmacokinetic profile of the drug may be altered, therefore a different dosing regimen could be required.

Methods: PK data of gentamycin were obtained from 82 hospitalized ICU patients. Dosing regimen was 7 mg/kg as a 1 hour infusion. Samples were collected before the administration, at the end of infusion and 8-16 hours after the administration. Fluorometry with TDX analyzer was used for the quantification of gentamycin concentrations. Using the software NONMEM (ver 7.3) with FOCEI method, first a basic model was determined by trying out different compartmental structural models and error models. Then statistically significant covariates were screened. The final PK model was validated using nonparametric bootstrapping and visual predictive check (VPC).

Results: : The final model was a one compartment model with combined error, parametrized as clearance (CL) and volume of distribution (V). The covariate model on CL was CL = θ1*(WT/84)θ3  *(CrCl/68)θ5  L/h and on V =θ2*(WT/84)θ4 L. Parameter estimates took the following values (SE in parentheses) θ1=3.56 L/h (5.4%) , θ2=51.9 L (2.6%)  , θ3=1.05 (30.9%) , θ4=0.54 (19.1%) and θ5=0.545 (18.5%) . Interindividual variability on CL and V was found to be 29.8% (17.7%) and 18.1% (31.5%) respectively, and residual error parameters were found σ1=21.5% and σ2=1.00 mg/L.  Bootstrap ran successfully in 1000 out of 1000 bootstraps, with mean θ1=3.57 (5.7%) L/h, θ2=51.9 (2.8%) L, θ3=1.19 (36.14%), θ4=0.54 (26.6%), θ5=0.554 (22.4%), ω1=0.272 (26.7%), ω2=0.141 (62.3%), σ1 =0.215 (16.2%) and σ2=0.93 mg/L (32.5%). The VPC plot demonstrated that the 5th, 50th and 95th percentiles of the data fell within the 95% CIs of the respective prediction intervals of the model, except a few points of the lower percentile.

Conclusion:  A population pharmacokinetic model for gentamycin in ICU patients was developed which includes the effect of age and weight and can be used to determine dosing regimens in these patients by calculating AUC/MIC target attainment probability through Monte Carlo simulations and considering appropriate AUC/MIC targets from literature.

Reference: PAGE 26 (2017) Abstr 7164 [www.page-meeting.org/?abstract=7164]
Poster: Drug/Disease modelling - Infection
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