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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Author: Martínez Illamola, Silvia
Format: doctoral thesis
Status:Published version
Publication Date:2013
Country:España
Institution:CBUC, CESCA
Repository:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/104267
Online Access:http://hdl.handle.net/10803/104267
Access Level:Open access
Keyword:Farmacocinètica
Farmacocinética
Pharmacokinetics
Amikacina
Amikacin
Antibiòtics
Antibióticos
Antibiotics
Neonatologia
Neonatología
Neonatology
Ciències de la Salut
615
id ES_67d41a32bdd3ee31bec9b903c8e43175
oai_identifier_str oai:www.tdx.cat:10803/104267
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Development of a population pharmacokinetic model to determine the optimal doses of amikacin in the treatment of neonatal sepsis
title Development of a population pharmacokinetic model to determine the optimal doses of amikacin in the treatment of neonatal sepsis
spellingShingle Development of a population pharmacokinetic model to determine the optimal doses of amikacin in the treatment of neonatal sepsis
Martínez Illamola, Silvia
Farmacocinètica
Farmacocinética
Pharmacokinetics
Amikacina
Amikacin
Antibiòtics
Antibióticos
Antibiotics
Neonatologia
Neonatología
Neonatology
Ciències de la Salut
615
title_short Development of a population pharmacokinetic model to determine the optimal doses of amikacin in the treatment of neonatal sepsis
title_full Development of a population pharmacokinetic model to determine the optimal doses of amikacin in the treatment of neonatal sepsis
title_fullStr Development of a population pharmacokinetic model to determine the optimal doses of amikacin in the treatment of neonatal sepsis
title_full_unstemmed Development of a population pharmacokinetic model to determine the optimal doses of amikacin in the treatment of neonatal sepsis
title_sort Development of a population pharmacokinetic model to determine the optimal doses of amikacin in the treatment of neonatal sepsis
dc.creator.none.fl_str_mv Martínez Illamola, Silvia
author Martínez Illamola, Silvia
author_facet Martínez Illamola, Silvia
author_role author
dc.contributor.none.fl_str_mv Colom Codina, Helena
Universitat de Barcelona. Departament de Farmàcia i Tecnologia Farmacèutica
dc.subject.none.fl_str_mv Farmacocinètica
Farmacocinética
Pharmacokinetics
Amikacina
Amikacin
Antibiòtics
Antibióticos
Antibiotics
Neonatologia
Neonatología
Neonatology
Ciències de la Salut
615
topic Farmacocinètica
Farmacocinética
Pharmacokinetics
Amikacina
Amikacin
Antibiòtics
Antibióticos
Antibiotics
Neonatologia
Neonatología
Neonatology
Ciències de la Salut
615
description 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.
publishDate 2013
dc.date.none.fl_str_mv 2013
2013
2014
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/104267
url http://hdl.handle.net/10803/104267
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 230 p.
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869409917745496064
spelling Development of a population pharmacokinetic model to determine the optimal doses of amikacin in the treatment of neonatal sepsisMartínez Illamola, SilviaFarmacocinèticaFarmacocinéticaPharmacokineticsAmikacinaAmikacinAntibiòticsAntibióticosAntibioticsNeonatologiaNeonatologíaNeonatologyCiències de la Salut615The 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.L’amikacina és un antibiòtic amb un efecte bactericida concentració depenent, inhibint la síntesi proteica, que és àmpliament utilitzat en el tractament de les sèpsies greus causades per bacils gram negatius. L’objectiu principal d’aquest estudi fou establir els paràmetres farmacocinètics de l’amikacina en nounats a partir de les dades de concentració sèrica obtingudes en la monitorització rutinària del fàrmac i identificar la influència de covariables i la variabilitat interindividual (VII) associada. Validar el model desenvolupat en una població externa, avaluar el règim de dosificació utilitzat i optimitzar les recomanacions de dosis inicials a administrar, van ser altres objectius. L’anàlisi farmacocinètic es va realitzar en una població de 149 individus utilitzant el programa NONMEM VII. La farmacocinètica de l’amikacina es va descriure amb un model bicompartimental amb entrada de fàrmac d’acord amb una cinètica d’ordre zero i eliminació de primer ordre. La VII va ser inclosa tant en l’aclariment (CL) com en el volum de distribució en el compartiment central (V1) i en el volum de distribució intercompartimental (Q), coeficient de variació (CV) del 16.39%, 25.23% i 40.08%, respectivament. El CV de l’error residual, modelitzat amb un component additiu i un proporcional, va ser del 6.97% i 15.34%, respectivament. El pes actual (WGT) i l’aclariment de creatinina (CLCR) van demostrar ser variables predictores del CL, i el WGT també del V1. Els valors estimats finals de l’CL i del V1 venen donats per TVCL=0.133•(CLCR/31.97)0.649•x(WGT/1880)0.752 i TVV1=0.837•(WGT/1880)1.09. L’avaluació del model final en una població externa, com a través de tècniques de validació internes, van demostrar la seva robustesa i capacitat de predicció. Diferents simulacions basades en les estimes farmacocinètiques finals del model van posar de manifest la influència de les covariables identificades en les concentracions sèriques d’amikacina, i van demostrar la capacitat del model per a establir dosis inicials òptimes del fàrmac pel tractament de les sèpsies neonatals. Aquest model podrà ser introduït en un programa Bayesià de farmacocinètica utilitzat en la pràctica clínica que permetrà optimitzar les dosis inicials a administrar i realitzar ajustos de dosi durant el tractament.Universitat de BarcelonaColom Codina, HelenaUniversitat de Barcelona. Departament de Farmàcia i Tecnologia Farmacèutica201320142013info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion230 p.application/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/10803/104267TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/1042672026-06-14T12:46:07Z
score 15,301603

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