Advertisement

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

Abstract

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 WORDS

CNS targeting delivery DB213 intranasal pharmacokinetic modeling 

Notes

Acknowledgments

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.

References

  1. 1.
    Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):614–28.  https://doi.org/10.1016/j.addr.2011.11.002.CrossRefPubMedGoogle Scholar
  2. 2.
    Qian S, Wo SK, Zuo Z. Pharmacokinetics and brain dispositions of tacrine and its major bioactive monohydroxylated metabolites in rats. J Pharm Biomed Anal. 2012;61:57–63.  https://doi.org/10.1016/j.jpba.2011.11.025.CrossRefPubMedGoogle Scholar
  3. 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. 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
  5. 5.
    Draghia R, Caillaud C, Manicom R, Pavirani A, Kahn A, Poenaru L. Gene delivery into the central nervous system by nasal instillation in rats. Gene Ther. 1995;2(6):418–23.PubMedGoogle Scholar
  6. 6.
    Danielyan L, Schäfer R, von Ameln-Mayerhofer A, Buadze M, Geisler J, Klopfer T, et al. Intranasal delivery of cells to the brain. Eur J Cell Biol. 2009;88(6):315–24.  https://doi.org/10.1016/j.ejcb.2009.02.001.CrossRefPubMedGoogle Scholar
  7. 7.
    Dahlin M, Bergman U, Jansson B, Björk E, Brittebo E. Transfer of dopamine in the olfactory pathway following nasal administration in mice. Pharm Res. 2000;17(6):737–42.  https://doi.org/10.1023/A:1007542618378.CrossRefPubMedGoogle Scholar
  8. 8.
    Wall A, Kågedal M, Bergström M, Jacobsson E, Nilsson D, Antoni G, et al. Distribution of zolmitriptan into the CNS in healthy volunteers. Drugs in R & D. 2005;6(3):139–47.  https://doi.org/10.2165/00126839-200506030-00002.CrossRefGoogle Scholar
  9. 9.
    Walker LC, Price DL, Voytko ML, Schenk DB. Labeling of cerebral amyloid in vivo with a monoclonal antibody. J Neuropathol Exp Neurol. 1994;53(4):377–83.  https://doi.org/10.1097/00005072-199407000-00009.CrossRefPubMedGoogle Scholar
  10. 10.
    Mittal D, Ali A, Md S, Baboota S, Sahni JK, Ali J. Insights into direct nose to brain delivery: current status and future perspective. Drug Deliv. 2014;21(2):75–86.  https://doi.org/10.3109/10717544.2013.838713.CrossRefPubMedGoogle Scholar
  11. 11.
    Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2(1):3–14.  https://doi.org/10.1602/neurorx.2.1.3.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kugel D, Kochs G, Obojes K, Roth J, Kobinger GP, Kobasa D, et al. Intranasal administration of alpha interferon reduces seasonal influenza a virus morbidity in ferrets. J Virol. 2009;83(8):3843–51.  https://doi.org/10.1128/JVI.02453-08.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Eriksson C, Bergman U, Franzen A, Sjöblom M, Brittebo E. Transfer of some carboxylic acids in the olfactory system following intranasal administration. J Drug Target. 1999;7(2):131–42.  https://doi.org/10.3109/10611869909085497.CrossRefPubMedGoogle Scholar
  14. 14.
    Westin UE, Boström E, Gråsjö J, Hammarlund-Udenaes M, Björk E. Direct nose-to-brain transfer of morphine after nasal administration to rats. Pharm Res. 2006;23(3):565–72.  https://doi.org/10.1007/s11095-006-9534-z.CrossRefPubMedGoogle Scholar
  15. 15.
    Kozlovskaya L, Abou-Kaoud M, Stepensky D. Quantitative analysis of drug delivery to the brain via nasal route. J Control Release. 2014;189:133–40.  https://doi.org/10.1016/j.jconrel.2014.06.053.CrossRefPubMedGoogle Scholar
  16. 16.
    Bagger MA, Bechgaard EA. Microdialysis model to examine nasal drug delivery and olfactory absorption in rats using lidocaine hydrochloride as a model drug. Int J Pharm. 2004;269(2):311–22.  https://doi.org/10.1016/j.ijpharm.2003.09.017.CrossRefPubMedGoogle Scholar
  17. 17.
    Bagger MA, Bechgaard E. The potential of nasal application for delivery to the central brain—a microdialysis study of fluorescein in rats. Eur J Pharm Sci. 2004;21(2-3):235–42.  https://doi.org/10.1016/j.ejps.2003.10.012.CrossRefPubMedGoogle Scholar
  18. 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. 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
  20. 20.
    Hammarlund-Udenaes M. Active-site concentrations of chemicals–are they a better predictor of effect than plasma/organ/tissue concentrations? Basic Clin Pharmacol Toxicol. 2010;106(3):215–20.  https://doi.org/10.1111/j.1742-7843.2009.00517.x.CrossRefPubMedGoogle Scholar
  21. 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. 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
  23. 23.
    Wang Q, Zhang Y, Qian S, Peng S, Zhang Q, Wong C, et al. Pharmacokinetics and brain uptake of HIV-1 replication inhibitor DB213 in Sprague-Dawley rats. J Pharm Biomed Anal. 2016;125:41–7.  https://doi.org/10.1016/j.jpba.2016.03.025.CrossRefPubMedGoogle Scholar
  24. 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. 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
  26. 26.
    Wong YC, Qian S, Zuo Z. Pharmacokinetic comparison between the long-term anesthetized, short-term anesthetized and conscious rat models in nasal drug delivery. Pharm Res. 2014;31(8):2107–23.  https://doi.org/10.1007/s11095-014-1312-8.CrossRefPubMedGoogle Scholar
  27. 27.
    Lee HB, Blaufox MD. Blood volume in the rat. J Nucl Med. 1985;26(1):72–6.PubMedGoogle Scholar
  28. 28.
    Stypinski D, Wiebe L, Tam Y, Mercer J, McEwan A. Effects of methoxyflurane anesthesia on the pharmacokinetics of 125 I-IAZA in sprague-dawley rats. Nucl Med Biol. 1999;26(8):959–65.  https://doi.org/10.1016/S0969-8051(99)00071-2.CrossRefPubMedGoogle Scholar
  29. 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
  30. 30.
    Cory Kalvass J, Maurer TS. Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm Drug Dispos. 2002;23(8):327–38.  https://doi.org/10.1002/bdd.325.CrossRefPubMedGoogle Scholar
  31. 31.
    Brouwer E, Verweij J, De Bruijn P, Loos WJ, Pillay M, Buijs D, et al. Measurement of fraction unbound paclitaxel in human plasma. Drug Metab Dispos. 2000;28(10):1141–5.PubMedGoogle Scholar
  32. 32.
    Friden M, Gupta A, Antonsson M, Bredberg U, Hammarlund-Udenaes M. In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metab Dispos. 2007;35(9):1711–9.  https://doi.org/10.1124/dmd.107.015222.CrossRefPubMedGoogle Scholar
  33. 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. 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
  35. 35.
    Johanson CE, Duncan JA, Klinge PM, Brinker T, Stopa EG, Silverberg GD. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res. 2008;5(1):10.  https://doi.org/10.1186/1743-8454-5-10.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143–51.  https://doi.org/10.1208/s12248-011-9255-z.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lindl KA, Marks DR, Kolson DL, Jordan-Sciutto KL. HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities. J NeuroImmune Pharmacol. 2010;5(3):294–309.  https://doi.org/10.1007/s11481-010-9205-z.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Nightingale S, Winston A, Letendre S, Michael BD, McArthur JC, Khoo S, et al. Controversies in HIV-associated neurocognitive disorders. Lancet Neurol. 2014;13(11):1139–51.  https://doi.org/10.1016/S1474-4422(14)70137-1.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 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. 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.
  41. 41.
    de Lange EC. Utility of CSF in translational neuroscience. J Pharmacokinet Pharmacodyn. 2013;40(3):315–26.  https://doi.org/10.1007/s10928-013-9301-9.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 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. 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.

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

Personalised recommendations