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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01316

Population pharmacokinetic/pharmacodynamic model-guided dosing optimization of a novel sedative HR7056 in Chinese healthy subjects

 Ying Zhou1*, Jinhua Wen1, Bei Hu2, Hongyun Wang2 and Ji Jiang2
  • 1First Affiliated Hospital of Nanchang University, China
  • 2Peking Union Medical College Hospital (CAMS), China

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 L min-1 and 0.27 L min-1, respectively. The population mean pharmacodynamic parameters were as follows: BIS, E0: 95.3; IC50: 503 ng mL-1; γ: 1.5; ke0: 0.0855 min-1; Imax: 47.9 and MOAA/S, IC50: 436 ng mL-1; γ: 1.5; ke0: 0.05 min-1; Imax: 27.9. The model simulation will enable maintenance doses to be given more accurately for future study (Clinical trial registration: NCT01970072).

Keywords: population pharmacodynamics, population pharmacokinetics, sedation, modeling, benzodiazepine

Received: 02 Aug 2018; Accepted: 29 Oct 2018.

Edited by:

Yurong Lai, Gilead (United States), United States

Reviewed by:

Zhihao Liu, University of Illinois at Chicago, United States
Bernd Meibohm, University of Tennessee Health Science Center (UTHSC), United States
Kazuya Ishida, Biogen Idec (United States), United States  

Copyright: © 2018 Zhou, Wen, Hu, Wang and Jiang. 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.

* Correspondence: Dr. Ying Zhou, First Affiliated Hospital of Nanchang University, Nanchang, China, zyyiva@163.com