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Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis

AIMS: Ketorolac is a nonsteroidal anti‐inflammatory racemic drug with analgesic effects only attributed to its S‐enantiomer. The aim of this study is to quantify enantiomer‐specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total k...

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Autores principales: Cloesmeijer, Michael E., van Esdonk, Michiel J., Lynn, Anne M., Smits, Anne, Tibboel, Dick, Daali, Youssef, Olkkola, Klaus T., Allegaert, Karel, Mian, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9328374/
https://www.ncbi.nlm.nih.gov/pubmed/32901947
http://dx.doi.org/10.1111/bcp.14547
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author Cloesmeijer, Michael E.
van Esdonk, Michiel J.
Lynn, Anne M.
Smits, Anne
Tibboel, Dick
Daali, Youssef
Olkkola, Klaus T.
Allegaert, Karel
Mian, Paola
author_facet Cloesmeijer, Michael E.
van Esdonk, Michiel J.
Lynn, Anne M.
Smits, Anne
Tibboel, Dick
Daali, Youssef
Olkkola, Klaus T.
Allegaert, Karel
Mian, Paola
author_sort Cloesmeijer, Michael E.
collection PubMed
description AIMS: Ketorolac is a nonsteroidal anti‐inflammatory racemic drug with analgesic effects only attributed to its S‐enantiomer. The aim of this study is to quantify enantiomer‐specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total ketorolac concentration remains equal between infants and adults or if a change in target racemic concentration should be considered when applied to infants. METHODS: Data were pooled from 5 different studies in adults, children and infants, with 1020 plasma concentrations following single intravenous ketorolac administration. An allometry‐based enantiomer‐specific population PK model was developed with NONMEM 7.3. Simulations were performed in typical adults and infants to investigate differences in S‐ and R‐ketorolac exposure. RESULTS: S‐ and R‐ketorolac PK were best described with a 3‐ and a 2‐compartment model, respectively. The allometry‐based PK parameters accounted for changes between populations. No maturation function of ketorolac clearance could be identified. All model parameters were estimated with adequate precision (relative standard error <50%). Single dose simulations showed that a previously established analgesic concentration at half maximal effect in adults of 0.37 mg/L, had a mean S‐ketorolac concentration of 0.057 mg/L, but a mean S‐ketorolac concentration of 0.046 mg/L in infants. To match the effective adult S‐ketorolac‐concentration (0.057 mg/L) in typical infants, the EC(50‐racemic) should be increased to 0.41 mg/L. CONCLUSION: Enantiomer‐specific changes in ketorolac PK yield different concentrations and S‐ and R‐ketorolac ratios between infants and adults at identical racemic concentrations. These PK findings should be considered when studies on maturational pharmacodynamics are considered.
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spelling pubmed-93283742022-07-30 Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis Cloesmeijer, Michael E. van Esdonk, Michiel J. Lynn, Anne M. Smits, Anne Tibboel, Dick Daali, Youssef Olkkola, Klaus T. Allegaert, Karel Mian, Paola Br J Clin Pharmacol Original Articles AIMS: Ketorolac is a nonsteroidal anti‐inflammatory racemic drug with analgesic effects only attributed to its S‐enantiomer. The aim of this study is to quantify enantiomer‐specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total ketorolac concentration remains equal between infants and adults or if a change in target racemic concentration should be considered when applied to infants. METHODS: Data were pooled from 5 different studies in adults, children and infants, with 1020 plasma concentrations following single intravenous ketorolac administration. An allometry‐based enantiomer‐specific population PK model was developed with NONMEM 7.3. Simulations were performed in typical adults and infants to investigate differences in S‐ and R‐ketorolac exposure. RESULTS: S‐ and R‐ketorolac PK were best described with a 3‐ and a 2‐compartment model, respectively. The allometry‐based PK parameters accounted for changes between populations. No maturation function of ketorolac clearance could be identified. All model parameters were estimated with adequate precision (relative standard error <50%). Single dose simulations showed that a previously established analgesic concentration at half maximal effect in adults of 0.37 mg/L, had a mean S‐ketorolac concentration of 0.057 mg/L, but a mean S‐ketorolac concentration of 0.046 mg/L in infants. To match the effective adult S‐ketorolac‐concentration (0.057 mg/L) in typical infants, the EC(50‐racemic) should be increased to 0.41 mg/L. CONCLUSION: Enantiomer‐specific changes in ketorolac PK yield different concentrations and S‐ and R‐ketorolac ratios between infants and adults at identical racemic concentrations. These PK findings should be considered when studies on maturational pharmacodynamics are considered. John Wiley and Sons Inc. 2020-10-09 2021-03 /pmc/articles/PMC9328374/ /pubmed/32901947 http://dx.doi.org/10.1111/bcp.14547 Text en © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Cloesmeijer, Michael E.
van Esdonk, Michiel J.
Lynn, Anne M.
Smits, Anne
Tibboel, Dick
Daali, Youssef
Olkkola, Klaus T.
Allegaert, Karel
Mian, Paola
Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis
title Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis
title_full Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis
title_fullStr Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis
title_full_unstemmed Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis
title_short Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis
title_sort impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: a pooled analysis
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9328374/
https://www.ncbi.nlm.nih.gov/pubmed/32901947
http://dx.doi.org/10.1111/bcp.14547
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