Development of a population pharmacokinetic model to determine the optimal doses of amikacin in the treatment of neonatal sepsis
The aim of this study was to establish the population pharmacokinetics of amikacin in newborns from serum concentration data obtained during the routine therapeutic drug monitoring and to explore the influence of patient covariates on drug disposition. To validate the developed model in into a exter...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2013 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/104267 |
| Acceso en línea: | http://hdl.handle.net/10803/104267 |
| Access Level: | acceso abierto |
| Palabra clave: | Farmacocinètica Farmacocinética Pharmacokinetics Amikacina Amikacin Antibiòtics Antibióticos Antibiotics Neonatologia Neonatología Neonatology Ciències de la Salut 615 |
| Sumario: | The aim of this study was to establish the population pharmacokinetics of amikacin in newborns from serum concentration data obtained during the routine therapeutic drug monitoring and to explore the influence of patient covariates on drug disposition. To validate the developed model in into a external dataset, belonging to the same population as the development group, to evaluate the current dose regimen and to optimize the first dose recommendations, were also aims of the study. Data were retrospectively collected for a study in newborns with postnatal age less than 90 days admitted in the neonatal unit of Vall Hebron (July 2000 to July 2006) who were treated with amikacin and with at least two serum concentration data of the aminoglycoside. Amikacin was administered as an i.v. infusion over 30 or 60 min. Blood samples were collected just before (“through”) and 1h after start of the infusion (“peak”). Demographic, clinical and amikacin dosing and concentration data were collected. Amikacin serum concentration measurements were done using fluorescence polarization immunoassay (TDx; Abbott Laboratories). Population PK analysis was performed from 149 newborns using the non linear mixed-effect approach (NONMEM version VII). The First order conditional estimation method (FOCE) with interaction was used throughough all the model bulding process.The PK of amikacin after iv administration was best described by a two-compartment linear disposition model. Between-patient variabilities expressed as coefficient of variation (CV%) were associated to total plasma clearance (CL) (16.39%) , central compartment distribution volume (V1) (25.23%) and distributional clearance (Q) (40.08%). Residual variability, modelled as a combined error model (proportional + additive), was 6.97% and 15.37%, respectively. Creatinine Clearance (CLCR) and body weight (WGT) were the most influential covariates in CL, and WGT was in V1. The final population model is: TVCL=0.133•(CLCR/31.97)0.649•x(WGT/1880)0.752 and TVV1=0.837•(WGT/1880)1.09. The external validation as well as th internal validation either through bootstrapping, or by Visual Predictive Check, prediction-corrected visual predictive check, posterior predictive check, or by normalised prediction distribution errors, suggested a good predictive ability for the developed model. The several simulations based on the final pharmacokinetic estimates of the model showed the influence of the covariates identified as significant in the serum amikacin concentrations, demonstrating the ability of the model to stablish optimal initial doses of amikacin for the treatment of neonatal sepsis. Due to the possibility of including the model in clinical pharmacokinetic software, the use of this model could improve the design of initial amikacin dosage in neonate populations and provide feedback adjustments of dosage regimens to achieve desired serum concentrations. |
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