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Population Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) in Preterm and Term Neonates: Model Development and External Evaluation.
Cook, Sarah F; Roberts, Jessica K; Samiee-Zafarghandy, Samira; Stockmann, Chris; King, Amber D; Deutsch, Nina; Williams, Elaine F; Allegaert, Karel; Wilkins, Diana G; Sherwin, Catherine M T; van den Anker, John N.
Afiliación
  • Cook SF; Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
  • Roberts JK; Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
  • Samiee-Zafarghandy S; Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA.
  • Stockmann C; Division of Neonatology, Department of Pediatrics, McMaster University, Hamilton, ON, Canada.
  • King AD; Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
  • Deutsch N; Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
  • Williams EF; Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
  • Allegaert K; Division of Anesthesiology, Sedation, and Perioperative Medicine, Children's National Health System, Washington, DC, USA.
  • Wilkins DG; Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA.
  • Sherwin CM; Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium.
  • van den Anker JN; Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
Clin Pharmacokinet ; 55(1): 107-19, 2016 Jan.
Article en En | MEDLINE | ID: mdl-26201306
OBJECTIVES: The aims of this study were to develop a population pharmacokinetic model for intravenous paracetamol in preterm and term neonates and to assess the generalizability of the model by testing its predictive performance in an external dataset. METHODS: Nonlinear mixed-effects models were constructed from paracetamol concentration-time data in NONMEM 7.2. Potential covariates included body weight, gestational age, postnatal age, postmenstrual age, sex, race, total bilirubin, and estimated glomerular filtration rate. An external dataset was used to test the predictive performance of the model through calculation of bias, precision, and normalized prediction distribution errors. RESULTS: The model-building dataset included 260 observations from 35 neonates with a mean gestational age of 33.6 weeks [standard deviation (SD) 6.6]. Data were well-described by a one-compartment model with first-order elimination. Weight predicted paracetamol clearance and volume of distribution, which were estimated as 0.348 L/h (5.5 % relative standard error; 30.8 % coefficient of variation) and 2.46 L (3.5 % relative standard error; 14.3 % coefficient of variation), respectively, at the mean subject weight of 2.30 kg. An external evaluation was performed on an independent dataset that included 436 observations from 60 neonates with a mean gestational age of 35.6 weeks (SD 4.3). The median prediction error was 10.1 % [95 % confidence interval (CI) 6.1-14.3] and the median absolute prediction error was 25.3 % (95 % CI 23.1-28.1). CONCLUSIONS: Weight predicted intravenous paracetamol pharmacokinetics in neonates ranging from extreme preterm to full-term gestational status. External evaluation suggested that these findings should be generalizable to other similar patient populations.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Analgésicos no Narcóticos / Acetaminofén / Modelos Biológicos Tipo de estudio: Evaluation_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans / Newborn Idioma: En Revista: Clin Pharmacokinet Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Analgésicos no Narcóticos / Acetaminofén / Modelos Biológicos Tipo de estudio: Evaluation_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans / Newborn Idioma: En Revista: Clin Pharmacokinet Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza