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Dose‐linearity of the pharmacokinetics of an intravenous [(14)C]midazolam microdose in children
AIMS: Drug disposition in children may vary from adults due to age‐related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [(14)C]...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783587/ https://www.ncbi.nlm.nih.gov/pubmed/31269280 http://dx.doi.org/10.1111/bcp.14047 |
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author | van Groen, Bianca D. Vaes, Wouter H. Park, B. Kevin Krekels, Elke H.J. van Duijn, Esther Kõrgvee, Lenne‐Triin Maruszak, Wioleta Grynkiewicz, Grzegorz Garner, R. Colin Knibbe, Catherijne A.J. Tibboel, Dick de Wildt, Saskia N. Turner, Mark A. |
author_facet | van Groen, Bianca D. Vaes, Wouter H. Park, B. Kevin Krekels, Elke H.J. van Duijn, Esther Kõrgvee, Lenne‐Triin Maruszak, Wioleta Grynkiewicz, Grzegorz Garner, R. Colin Knibbe, Catherijne A.J. Tibboel, Dick de Wildt, Saskia N. Turner, Mark A. |
author_sort | van Groen, Bianca D. |
collection | PubMed |
description | AIMS: Drug disposition in children may vary from adults due to age‐related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [(14)C]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose. METHODS: Preterm to 2‐year‐old infants admitted to the intensive care unit received [(14)C]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [(14)C]midazolam and [(14)C]1‐hydroxy‐midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed. RESULTS: Of 15 infants (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), 6 received a microtracer and 9 a microdose of [(14)C]midazolam (111 Bq kg(−1); 37.6 ng kg(−1)). In a 2‐compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [(14)C]1‐OH‐midazolam/[(14)C]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses. CONCLUSION: Our data support the dose linearity of the PK of an IV [(14)C]midazolam microdose in children. Hence, a [(14)C]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children. |
format | Online Article Text |
id | pubmed-6783587 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-67835872019-10-17 Dose‐linearity of the pharmacokinetics of an intravenous [(14)C]midazolam microdose in children van Groen, Bianca D. Vaes, Wouter H. Park, B. Kevin Krekels, Elke H.J. van Duijn, Esther Kõrgvee, Lenne‐Triin Maruszak, Wioleta Grynkiewicz, Grzegorz Garner, R. Colin Knibbe, Catherijne A.J. Tibboel, Dick de Wildt, Saskia N. Turner, Mark A. Br J Clin Pharmacol Original Articles AIMS: Drug disposition in children may vary from adults due to age‐related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [(14)C]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose. METHODS: Preterm to 2‐year‐old infants admitted to the intensive care unit received [(14)C]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [(14)C]midazolam and [(14)C]1‐hydroxy‐midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed. RESULTS: Of 15 infants (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), 6 received a microtracer and 9 a microdose of [(14)C]midazolam (111 Bq kg(−1); 37.6 ng kg(−1)). In a 2‐compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [(14)C]1‐OH‐midazolam/[(14)C]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses. CONCLUSION: Our data support the dose linearity of the PK of an IV [(14)C]midazolam microdose in children. Hence, a [(14)C]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children. John Wiley and Sons Inc. 2019-07-30 2019-10 /pmc/articles/PMC6783587/ /pubmed/31269280 http://dx.doi.org/10.1111/bcp.14047 Text en © 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles van Groen, Bianca D. Vaes, Wouter H. Park, B. Kevin Krekels, Elke H.J. van Duijn, Esther Kõrgvee, Lenne‐Triin Maruszak, Wioleta Grynkiewicz, Grzegorz Garner, R. Colin Knibbe, Catherijne A.J. Tibboel, Dick de Wildt, Saskia N. Turner, Mark A. Dose‐linearity of the pharmacokinetics of an intravenous [(14)C]midazolam microdose in children |
title | Dose‐linearity of the pharmacokinetics of an intravenous [(14)C]midazolam microdose in children |
title_full | Dose‐linearity of the pharmacokinetics of an intravenous [(14)C]midazolam microdose in children |
title_fullStr | Dose‐linearity of the pharmacokinetics of an intravenous [(14)C]midazolam microdose in children |
title_full_unstemmed | Dose‐linearity of the pharmacokinetics of an intravenous [(14)C]midazolam microdose in children |
title_short | Dose‐linearity of the pharmacokinetics of an intravenous [(14)C]midazolam microdose in children |
title_sort | dose‐linearity of the pharmacokinetics of an intravenous [(14)c]midazolam microdose in children |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783587/ https://www.ncbi.nlm.nih.gov/pubmed/31269280 http://dx.doi.org/10.1111/bcp.14047 |
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