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Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults

BACKGROUND: The application of modeling and simulation approaches in clinical pharmacology studies has gained momentum over the last 20 years. OBJECTIVES: The objective of this study was to develop six empirical models from clearance data obtained from children aged > 2 years and adults to evalua...

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Autor principal: Mahmood, Iftekhar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067721/
https://www.ncbi.nlm.nih.gov/pubmed/31820365
http://dx.doi.org/10.1007/s40268-019-00291-2
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author Mahmood, Iftekhar
author_facet Mahmood, Iftekhar
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description BACKGROUND: The application of modeling and simulation approaches in clinical pharmacology studies has gained momentum over the last 20 years. OBJECTIVES: The objective of this study was to develop six empirical models from clearance data obtained from children aged > 2 years and adults to evaluate the suitability of the models to predict drug clearance in children aged ≤ 2 years (preterm, term, and infants). METHODS: Ten drugs were included in this study and administered intravenously: alfentanil, amikacin, busulfan, cefetamet, meperidine, oxycodone, propofol, sufentanil, theophylline, and tobramycin. These drugs were selected according to the availability of individual subjects’ weight, age, and clearance data (concentration–time data for these drugs were not available to the author). The chosen drugs are eliminated by extensive metabolism by either the renal route or both the renal and hepatic routes. The six empirical models were (1) age and body weight-dependent sigmoidal maximum possible effect (E(max)) maturation model, (2) body weight-dependent sigmoidal E(max) model, (3) uridine 5′-diphospho [body weight-dependent allometric exponent model (BDE)], (4) age-dependent allometric exponent model (ADE), (5) a semi-physiological model, and (6) an allometric model developed from children aged > 2 years to adults. The model-predicted clearance values were compared with observed clearance values in an individual child. In this analysis, a prediction error of ≤ 50% for mean or individual clearance values was considered acceptable. RESULTS: Across all age groups and the ten drugs, data for 282 children were compared between observed and model-predicted clearance values. The validation data consisted of 33 observations (sum of different age groups for ten drugs). Only three of the six models (body weight-dependent sigmoidal E(max) model, ADE, and semi-physiological model) provided reasonably accurate predictions of clearance (> 80% observation with ≤ 50% prediction error) in children aged ≤ 2 years. In most instances, individual predicted clearance values were erratic (as indicated by % error) and were not in agreement with the observed clearance values. CONCLUSIONS: The study indicated that simple empirical models can provide more accurate results than complex empirical models. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40268-019-00291-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-70677212020-03-23 Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults Mahmood, Iftekhar Drugs R D Original Research Article BACKGROUND: The application of modeling and simulation approaches in clinical pharmacology studies has gained momentum over the last 20 years. OBJECTIVES: The objective of this study was to develop six empirical models from clearance data obtained from children aged > 2 years and adults to evaluate the suitability of the models to predict drug clearance in children aged ≤ 2 years (preterm, term, and infants). METHODS: Ten drugs were included in this study and administered intravenously: alfentanil, amikacin, busulfan, cefetamet, meperidine, oxycodone, propofol, sufentanil, theophylline, and tobramycin. These drugs were selected according to the availability of individual subjects’ weight, age, and clearance data (concentration–time data for these drugs were not available to the author). The chosen drugs are eliminated by extensive metabolism by either the renal route or both the renal and hepatic routes. The six empirical models were (1) age and body weight-dependent sigmoidal maximum possible effect (E(max)) maturation model, (2) body weight-dependent sigmoidal E(max) model, (3) uridine 5′-diphospho [body weight-dependent allometric exponent model (BDE)], (4) age-dependent allometric exponent model (ADE), (5) a semi-physiological model, and (6) an allometric model developed from children aged > 2 years to adults. The model-predicted clearance values were compared with observed clearance values in an individual child. In this analysis, a prediction error of ≤ 50% for mean or individual clearance values was considered acceptable. RESULTS: Across all age groups and the ten drugs, data for 282 children were compared between observed and model-predicted clearance values. The validation data consisted of 33 observations (sum of different age groups for ten drugs). Only three of the six models (body weight-dependent sigmoidal E(max) model, ADE, and semi-physiological model) provided reasonably accurate predictions of clearance (> 80% observation with ≤ 50% prediction error) in children aged ≤ 2 years. In most instances, individual predicted clearance values were erratic (as indicated by % error) and were not in agreement with the observed clearance values. CONCLUSIONS: The study indicated that simple empirical models can provide more accurate results than complex empirical models. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40268-019-00291-2) contains supplementary material, which is available to authorized users. Springer International Publishing 2019-12-09 2020-03 /pmc/articles/PMC7067721/ /pubmed/31820365 http://dx.doi.org/10.1007/s40268-019-00291-2 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research Article
Mahmood, Iftekhar
Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults
title Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults
title_full Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults
title_fullStr Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults
title_full_unstemmed Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults
title_short Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults
title_sort extrapolation of drug clearance in children ≤ 2 years of age from empirical models using data from children (> 2 years) and adults
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067721/
https://www.ncbi.nlm.nih.gov/pubmed/31820365
http://dx.doi.org/10.1007/s40268-019-00291-2
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