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Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs
The primary purpose of this study was to assess the translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system (CNS) active drugs. As a part of this, IBs were reviewed on reporting quality. Investigator’s Brochures (IBs) of studies...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977891/ https://www.ncbi.nlm.nih.gov/pubmed/36859342 http://dx.doi.org/10.1038/s41398-023-02353-1 |
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author | Ferreira, Guilherme S. Dijkstra, Francis M. Veening-Griffioen, Désirée H. Boon, Wouter P. C. Schellekens, Huub Moors, Ellen H. M. van Meer, Peter J. K. Stuurman, Frederik E. van Gerven, Joop M. A. |
author_facet | Ferreira, Guilherme S. Dijkstra, Francis M. Veening-Griffioen, Désirée H. Boon, Wouter P. C. Schellekens, Huub Moors, Ellen H. M. van Meer, Peter J. K. Stuurman, Frederik E. van Gerven, Joop M. A. |
author_sort | Ferreira, Guilherme S. |
collection | PubMed |
description | The primary purpose of this study was to assess the translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system (CNS) active drugs. As a part of this, IBs were reviewed on reporting quality. Investigator’s Brochures (IBs) of studies performed at the Centre for Human Drug Research (CHDR) reporting statistically significant results of CNS activity related to the drug’s mechanism of action were included. The quality of IBs was assessed based on the presence of a rationale for the chosen animal model, completeness of pharmacokinetic (PK) results in reporting and internal validity information of the preclinical evidence. The IB-derisk tool was used to generate preclinical and early clinical data overviews data. For each compound, the overlap between pharmacologically active dose ranges and well-tolerated levels was calculated for three pharmacokinetic (PK) parameters: human equivalent dose (HED), maximum plasma concentration (C(max)) and area under the curve (AUC). Twenty-five IBs were included. In general, the quality of reporting in IBs was assessed as poor. About a third of studies did not explore the entire concentration-effect curve (pre)clinically. Single dose tolerability ranges were most accurately predicted by C(max). Human equivalent dose and AUC were the best predictors of pharmacologically active ranges. Tolerable and pharmacologically active dose ranges in healthy volunteers can be reasonably well predicted from preclinical data with the IB-derisk tool. The translatability of preclinical studies can be improved by applying a higher reporting standard in IBs including comparable PK measurements across all preclinical and clinical studies. |
format | Online Article Text |
id | pubmed-9977891 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-99778912023-03-03 Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs Ferreira, Guilherme S. Dijkstra, Francis M. Veening-Griffioen, Désirée H. Boon, Wouter P. C. Schellekens, Huub Moors, Ellen H. M. van Meer, Peter J. K. Stuurman, Frederik E. van Gerven, Joop M. A. Transl Psychiatry Review Article The primary purpose of this study was to assess the translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system (CNS) active drugs. As a part of this, IBs were reviewed on reporting quality. Investigator’s Brochures (IBs) of studies performed at the Centre for Human Drug Research (CHDR) reporting statistically significant results of CNS activity related to the drug’s mechanism of action were included. The quality of IBs was assessed based on the presence of a rationale for the chosen animal model, completeness of pharmacokinetic (PK) results in reporting and internal validity information of the preclinical evidence. The IB-derisk tool was used to generate preclinical and early clinical data overviews data. For each compound, the overlap between pharmacologically active dose ranges and well-tolerated levels was calculated for three pharmacokinetic (PK) parameters: human equivalent dose (HED), maximum plasma concentration (C(max)) and area under the curve (AUC). Twenty-five IBs were included. In general, the quality of reporting in IBs was assessed as poor. About a third of studies did not explore the entire concentration-effect curve (pre)clinically. Single dose tolerability ranges were most accurately predicted by C(max). Human equivalent dose and AUC were the best predictors of pharmacologically active ranges. Tolerable and pharmacologically active dose ranges in healthy volunteers can be reasonably well predicted from preclinical data with the IB-derisk tool. The translatability of preclinical studies can be improved by applying a higher reporting standard in IBs including comparable PK measurements across all preclinical and clinical studies. Nature Publishing Group UK 2023-03-01 /pmc/articles/PMC9977891/ /pubmed/36859342 http://dx.doi.org/10.1038/s41398-023-02353-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Review Article Ferreira, Guilherme S. Dijkstra, Francis M. Veening-Griffioen, Désirée H. Boon, Wouter P. C. Schellekens, Huub Moors, Ellen H. M. van Meer, Peter J. K. Stuurman, Frederik E. van Gerven, Joop M. A. Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs |
title | Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs |
title_full | Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs |
title_fullStr | Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs |
title_full_unstemmed | Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs |
title_short | Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs |
title_sort | translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977891/ https://www.ncbi.nlm.nih.gov/pubmed/36859342 http://dx.doi.org/10.1038/s41398-023-02353-1 |
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