The AAPS Journal

, 20:23 | Cite as

Demonstration of Direct Nose-to-Brain Transport of Unbound HIV-1 Replication Inhibitor DB213 Via Intranasal Administration by Pharmacokinetic Modeling

  • Qianwen Wang
  • Yufeng Zhang
  • Chun-Ho Wong
  • H.Y. Edwin Chan
  • Zhong Zuo
Research Article


Intranasal administration could be an attractive alternative route of administration for the delivery of drugs to the central nervous system (CNS). However, there are always doubts about the direct transport of therapeutics from nasal cavity to the CNS since there are only limited studies on the understanding of direct nose-to-brain transport. Therefore, this study aimed to (1) investigate the existence of nose-to-brain transport of intranasally administered HIV-1 replication inhibitor DB213 and (2) assess the direct nose-to-brain transport of unbound HIV-1 replication inhibitor DB213 quantitatively by a pharmacokinetic approach. Plasma samples were collected up to 6 h post-dosing after administration via intranasal or intravenous route at three bolus doses. In the brain-uptake study, the plasma, whole brain, and cerebrospinal fluid (CSF) were sampled between 15 min and 8 h post-dosing. All samples were analyzed with LC/MS/MS. Plasma, CSF, and brain concentration versus time profiles were analyzed with nonlinear mixed-effect modeling. Structural model building was performed by NONMEM (version VII, level 2.0). Intranasal administration showed better potential to deliver HIV-1 replication inhibitor DB213 to the brain with 290-fold higher brain to plasma ratio compared with intravenous administration. Based on that, a model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) was developed and demonstrated 72.4% of total absorbed unbound HIV-1 replication inhibitor DB213 after intranasal administration was transported directly into the brain through nose-to-brain pathway.


CNS targeting delivery DB213 intranasal pharmacokinetic modeling 



This work was generously supported by the Lui Che Woo Institute of Innovative Medicine BRAIN Initiative (Project Number 8303404) and Gerald Choa Neuroscience Centre (Project Number 7105306), Faculty of Medicine, The Chinese University of Hong Kong. The authors are grateful to Prof. Margareta Hammarlund-Udenaes from Translational PKPD Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, for her valuable suggestions to the data analyses and manuscript.


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Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Qianwen Wang
    • 1
  • Yufeng Zhang
    • 1
  • Chun-Ho Wong
    • 2
  • H.Y. Edwin Chan
    • 2
    • 3
  • Zhong Zuo
    • 1
  1. 1.School of PharmacyThe Chinese University of Hong KongHong KongPeople’s Republic of China
  2. 2.School of Life SciencesThe Chinese University of Hong KongHong KongPeople’s Republic of China
  3. 3.Gerald Choa Neuroscience CentreThe Chinese University of Hong KongHong KongPeople’s Republic of China

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