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Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects

HR7056 is a new benzodiazepine, showing more faster acting onset and recovery than currently available short-acting sedatives. To avoid inadequate anesthesia and predict return of cognition, allowing for immediate neurological evaluation, HR7056 pharmacokinetics and pharmacodynamics were characteriz...

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Autores principales: Zhou, Ying, Hu, Pei, Huang, Yuguang, Sang, Nuoer, Song, Kaicheng, Wang, Hongyun, Wen, Jinhua, Jiang, Ji, Chen, Xia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252322/
https://www.ncbi.nlm.nih.gov/pubmed/30510509
http://dx.doi.org/10.3389/fphar.2018.01316
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author Zhou, Ying
Hu, Pei
Huang, Yuguang
Sang, Nuoer
Song, Kaicheng
Wang, Hongyun
Wen, Jinhua
Jiang, Ji
Chen, Xia
author_facet Zhou, Ying
Hu, Pei
Huang, Yuguang
Sang, Nuoer
Song, Kaicheng
Wang, Hongyun
Wen, Jinhua
Jiang, Ji
Chen, Xia
author_sort Zhou, Ying
collection PubMed
description HR7056 is a new benzodiazepine, showing more faster acting onset and recovery than currently available short-acting sedatives. To avoid inadequate anesthesia and predict return of cognition, allowing for immediate neurological evaluation, HR7056 pharmacokinetics and pharmacodynamics were characterized in Chinese healthy subjects. We report on modeling of the data and simulations of dosage regimens for future study. Up to 63 subjects were evaluated, using Bispectral Index (BIS) and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) as pharmacodynamics endpoints. A three-compartment model best described HR7056 pharmacokinetics. Total clearance was 1.49 L min(−1), central volume was 2.1 L, inter-compartmental clearances were 0.96 and 0.27 L min(−1), respectively. The population mean pharmacodynamic parameters were as follows: BIS, E(0): 95.3; IC(50): 503 ng mL(−1); γ: 1.5; k(e0): 0.0855 min(−1); I(max): 47.9 and MOAA/S, IC(50): 436 ng mL(−1); γ: 1.5; k(e0): 0.05 min(−1); I(max): 27.9. The model simulation will enable maintenance doses to be given more accurately for future study. Clinical Trial Registration: identifier: NCT01970072
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spelling pubmed-62523222018-12-03 Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects Zhou, Ying Hu, Pei Huang, Yuguang Sang, Nuoer Song, Kaicheng Wang, Hongyun Wen, Jinhua Jiang, Ji Chen, Xia Front Pharmacol Pharmacology HR7056 is a new benzodiazepine, showing more faster acting onset and recovery than currently available short-acting sedatives. To avoid inadequate anesthesia and predict return of cognition, allowing for immediate neurological evaluation, HR7056 pharmacokinetics and pharmacodynamics were characterized in Chinese healthy subjects. We report on modeling of the data and simulations of dosage regimens for future study. Up to 63 subjects were evaluated, using Bispectral Index (BIS) and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) as pharmacodynamics endpoints. A three-compartment model best described HR7056 pharmacokinetics. Total clearance was 1.49 L min(−1), central volume was 2.1 L, inter-compartmental clearances were 0.96 and 0.27 L min(−1), respectively. The population mean pharmacodynamic parameters were as follows: BIS, E(0): 95.3; IC(50): 503 ng mL(−1); γ: 1.5; k(e0): 0.0855 min(−1); I(max): 47.9 and MOAA/S, IC(50): 436 ng mL(−1); γ: 1.5; k(e0): 0.05 min(−1); I(max): 27.9. The model simulation will enable maintenance doses to be given more accurately for future study. Clinical Trial Registration: identifier: NCT01970072 Frontiers Media S.A. 2018-11-19 /pmc/articles/PMC6252322/ /pubmed/30510509 http://dx.doi.org/10.3389/fphar.2018.01316 Text en Copyright © 2018 Zhou, Hu, Huang, Sang, Song, Wang, Wen, Jiang and Chen. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhou, Ying
Hu, Pei
Huang, Yuguang
Sang, Nuoer
Song, Kaicheng
Wang, Hongyun
Wen, Jinhua
Jiang, Ji
Chen, Xia
Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects
title Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects
title_full Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects
title_fullStr Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects
title_full_unstemmed Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects
title_short Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects
title_sort population pharmacokinetic/pharmacodynamic model-guided dosing optimization of a novel sedative hr7056 in chinese healthy subjects
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252322/
https://www.ncbi.nlm.nih.gov/pubmed/30510509
http://dx.doi.org/10.3389/fphar.2018.01316
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