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

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.