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.
KEY WORDSCNS 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.
- 3.Freiherr J, Hallschmid M, Frey WH II, Brünner YF, Chapman CD, Hölscher C, et al. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS drugs. 2013;27(7):505–14. https://doi.org/10.1007/s40263-013-0076-8.CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Thorne R, Pronk G, Padmanabhan V, Frey W II. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience. 2004;127(2):481–96. https://doi.org/10.1016/j.neuroscience.2004.05.029.CrossRefPubMedGoogle Scholar
- 18.Charlton ST, Whetstone J, Fayinka ST, Read KD, Illum L, Davis SS. Evaluation of direct transport pathways of glycine receptor antagonists and an angiotensin antagonist from the nasal cavity to the central nervous system in the rat model. Pharm Res. 2008;25(7):1531–43. https://doi.org/10.1007/s11095-008-9550-2.CrossRefPubMedGoogle Scholar
- 19.Uchida M, Katoh T, Mori M, Maeno T, Ohtake K, Kobayashi J, et al. Intranasal administration of milnacipran in rats: evaluation of the transport of drugs to the systemic circulation and central nervous system and the pharmacological effect. Biol Pharm Bull. 2011;34(5):740–7. https://doi.org/10.1248/bpb.34.740.CrossRefPubMedGoogle Scholar
- 21.Kalvass JC, Olson ER, Cassidy MP, Selley DE, Pollack GM. Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical data. J Pharmacol Exp Ther. 2007;323(1):346–55. https://doi.org/10.1124/jpet.107.119560.CrossRefPubMedGoogle Scholar
- 22.Stevens J, Ploeger BA, van der Graaf PH, Danhof M, de Lange EC. Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration. Drug Metab Dispos. 2011;39(12):2275–82. https://doi.org/10.1124/dmd.111.040782.CrossRefPubMedGoogle Scholar
- 24.Guo Z, Hong Z, Dong W, Deng C, Zhao R, Xu J, et al. PM2. 5-induced oxidative stress and mitochondrial damage in the nasal mucosa of rats. Int J Environ Res Public Health. 2017;14(2):134. https://doi.org/10.3390/ijerph14020134.
- 25.Yamamoto Y, Välitalo PA, van den Berg D, Hartman R, van den Brink W, Wong YC, et al. A generic multi-compartmental CNS distribution model structure for 9 drugs allows prediction of human brain target site concentrations. Pharm Res. 2016:1–19.Google Scholar
- 29.Kalvass JC, Maurer TS, Pollack GM. Use of plasma and brain unbound fractions to assess the extent of brain distribution of 34 drugs: comparison of unbound concentration ratios to in vivo p-glycoprotein efflux ratios. Drug Metab Dispos. 2007;35(4):660–6. https://doi.org/10.1124/dmd.106.012294.CrossRefPubMedGoogle Scholar
- 33.Modi ME, Majchrzak MJ, Fonseca KR, Doran A, Osgood S, Vanase-Frawley M, et al. Peripheral administration of a long-acting peptide oxytocin receptor agonist inhibits fear-induced freezing. J Pharmacol Exp Ther. 2016;358(2):164–72. https://doi.org/10.1124/jpet.116.232702.CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Hammarlund-Udenaes M. Pharmacokinetic concepts in brain drug delivery. In: Hammarlund-Udenaes M, de Lange E, Thorne RG, editors. Drug Delivery to the Brain. New York: Springer. 2014:127–161.Google Scholar
- 39.Fridén M, Winiwarter S, Jerndal G, Bengtsson O, Wan H, Bredberg U, et al. Structure− brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids. J Med Chem. 2009;52(20):6233–43. https://doi.org/10.1021/jm901036q.CrossRefPubMedGoogle Scholar
- 40.Terasaki T, Deguchi Y, Sato H, Hirai KI, Tsuji A. In vivo transport of a dynorphin-like analgesic peptide, E-2078, through the blood–brain barrier: an application of brain microdialysis. Pharm Res. 1991;8(7):815–20. https://doi.org/10.1023/A:1015882924470.
- 42.Somjen GG. Ions and water in the brain. In: Somjen GG, editor. Ions in the brain: normal function, seizures, and stroke. Oxford: Oxford University Press. 2004:6–7.Google Scholar
- 43.Merkus FWHM, van den Berg MP. Can nasal drug delivery bypass the blood-brain barrier? Drugs R D. 2007;8(3):133–44. https://doi.org/10.2165/00126839-200708030-00001.