The Pharmacokinetics of Drug Delivery to the Upper Nasal Space: A Review of INP105 Development
Main Article Content
Abstract
Nasal drug delivery presents a potential opportunity for achieving rapid, extensive drug absorption via a nonoral route by 1) avoiding degradation within the gastrointestinal tract and first-pass metabolism in the liver and 2) facilitating faster onset via rapid absorption into the bloodstream. However, the site of drug deposition within the nasal cavity may impact drug pharmacokinetics. Precision Olfactory Delivery (POD®) by Impel Pharmaceuticals Inc. is a new technology that provides handheld, manually actuated, propellant-powered drug delivery to the upper nasal space for rapid and efficient absorption. Rapid onset of effect can be a major advantage in many clinical applications where quick and effective administration is needed (eg, alleviating agitation in emergency settings or reducing debilitating migraine symptoms). Here, we review the pharmacokinetic profile of INP105, which is being developed to deliver olanzapine (OLZ) by POD to treat agitation in patients with autism. Because formulation can play a large role in the pharmacokinetic profile of a nasally administered drug, we provide a comprehensive review of both published and previously unpublished preclinical data outlining how the INP105 formulation was developed and optimized for study in humans. Multiple formulation carriers and excipients were tested to find a stable INP105 formulation with a desirable nasal absorption profile. Because the nasal architecture in nonhuman primates (NHPs) is similar to humans, the pharmacokinetics and tolerability of an INP105 combination product (NHP-INP105) using a clinical formulation combined with a device specifically designed for NHPs has been investigated in preclinical NHP studies, providing translational data for human studies and the pathway for testing novel products and formulations. The pharmacokinetics and tolerability of INP105 were then evaluated in an early clinical study in humans, demonstrating favorable pharmacokinetic and pharmacodynamic profiles. In this review, we aim to illustrate how delivery of therapeutics to the upper nasal space using POD, such as with agents like INP105, has the potential to optimize nasal delivery and unlock the potential of delivery-limited drugs to provide patients with rapid onset of effect, ease of use, and convenience.
Keywords:
Precision Olfactory Delivery, upper nasal space, pharmacokinetics, translational research, nasal delivery, INP105
Article Details
How to Cite
SHREWSBURY, Stephen Bevan et al.
The Pharmacokinetics of Drug Delivery to the Upper Nasal Space: A Review of INP105 Development.
Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2971>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v10i9.2971.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Vugmeyster Y, Harrold J, Xu X. Absorption, distribution, metabolism, and excretion (adme) studies of biotherapeutics for autoimmune and inflammatory conditions. AAPS J. 2012;14(4):714-727. DOI: 10.1208/s12248-012-9385-y
2. Tang C, Prueksaritanont T. Use of in vivo animal models to assess pharmacokinetic drug-drug interactions. Pharm Res. 2010;27(9):1772-1787. DOI: 10.1007/s11095-010-0157-z
3. Yacobi A, Skelly JP, Shah VP, Benet LZ, eds. Integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. Springer; 1993.
4. Tuntland T, Ethell B, Kosaka T, et al. Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at novartis institute of biomedical research. Front Pharmacol. 2014;5:174. DOI: 10.3389/fphar.2014.00174
5. Price G, Patel DA. Drug bioavailability. In: Statpearls publishing. Treasure Island, FL 2020.
6. Jin JF, Zhu LL, Chen M, et al. The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection. Patient Prefer Adherence. 2015;9:923-942. DOI: 10.2147/PPA.S87271
7. Shrewsbury S, Hocevar-Trnka J, Hoekman J. Drug delivery via the upper nasal space: A novel route for anesthesiologists, intensivists and emergency department physicians? J Clin Anesth Intensive Care. 2021;2(1):8-14.
8. Djupesland PG, Messina JC, Mahmoud RA. Breath powered nasal delivery: A new route to rapid headache relief. Headache. 2013;53(Suppl 2):72-84. DOI: 10.1111/head.12186
9. Homayun B, Lin X, Choi HJ. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics. 2019;11(3):129. DOI: 10.3390/pharmaceutics11030129
10. Citrome L. Addressing the need for rapid treatment of agitation in schizophrenia and bipolar disorder: Focus on inhaled loxapine as an alternative to injectable agents. Therapeutics and clinical risk management. 2013;9:235-245. DOI: 10.2147/TCRM.S31484
11. Rech MA, Barbas B, Chaney W, Greenhalgh E, Turck C. When to pick the nose: Out-of-hospital and emergency department intranasal administration of medications. Ann Emerg Med. 2017;70(2):203-211. DOI: 10.1016/j.annemergmed.2017.02.015
12. Simonet C, Tolosa E, Camara A, Valldeoriola F. Emergencies and critical issues in parkinson’s disease. Pract Neurol. 2020;20(1):15-25. DOI: 10.1136/practneurol-2018-002075
13. Lipton RB, Munjal S, Buse DC, et al. Unmet acute treatment needs from the 2017 Migraine In America Symptoms And Treatment Study. Headache. 2019;59(8):1310-1323. DOI: 10.1111/head.13588
14. Detke HC, Millen BA, Zhang Q, et al. Rapid onset of effect of galcanezumab for the prevention of episodic migraine: Analysis of the evolve studies. Headache. 2020;60(2):348-359. DOI: 10.1111/head.13691
15. Rygg A, Hindle M, Longest PW. Absorption and clearance of pharmaceutical aerosols in the human nose: Effects of nasal spray suspension particle size and properties. Pharm Res. 2016;33(4):909-921. DOI: 10.1007/s11095-015-1837-5
16. Djupesland PG. Nasal drug delivery devices: Characteristics and performance in a clinical perspective-a review. Drug Deliv Transl Res. 2013;3(1):42-62. DOI: 10.1007/s13346-012-0108-9
17. Dhuria SV, Hanson LR, Frey WH, II. Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. J Pharm Sci. 2010;99(4):1654-1673. DOI: 10.1002/jps.21924
18. Mignani S, Shi X, Karpus A, Majoral JP. Non-invasive intranasal administration route directly to the brain using dendrimer nanoplatforms: An opportunity to develop new cns drugs. Eur J Med Chem. 2021;209:112905. DOI: 10.1016/j.ejmech.2020.112905
19. Kellerman DJ, Forst A, Combs DL, Borland S, Kori S. Assessment of the consistency of absorption of dihydroergotamine following oral inhalation: Pooled results from four clinical studies. J Aerosol Med Pulm Drug Deliv. 2013;26(5):297-306. DOI: 10.1089/jamp.2012.0999
20. Martin V, Hoekman J, Aurora SK, Shrewsbury SB. Nasal delivery of acute medications for migraine: The upper versus lower nasal space. J Clin Med. 2021;10(11)2468. DOI: 10.3390/jcm10112468
21. Musumeci T, Bonaccorso A, Puglisi G. Epilepsy disease and nose-to-brain delivery of polymeric nanoparticles: An overview. Pharmaceutics. 2019;11(3):118. DOI: 10.3390/pharmaceutics11030118
22. Miller JL, Ashford JW, Archer SM, Rudy AC, Wermeling DP. Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: A pilot pharmacokinetic study. Pharmacotherapy. 2008;28(7):875-882. DOI: 10.1592/phco.28.7.875
23. Hoekman J, Ray S, Aurora SK, Shrewsbury SB. The upper nasal space—a novel delivery route ideal for central nervous system drugs. US Neurol. 2020;16(1):25-31.
24. Gänger S, Schindowski K. Tailoring formulations for intranasal nose-to-brain delivery: A review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa. Pharmaceutics. 2018;10(3):116. DOI: 10.3390/pharmaceutics10030116
25. Djupesland PG, Messina JC, Mahmoud RA. The nasal approach to delivering treatment for brain diseases: An anatomic, physiologic, and delivery technology overview. Ther Deliv. 2014;5(6):709-733. DOI: 10.4155/tde.14.41
26. Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life Sci. 2018;195:44-52. DOI: 10.1016/j.lfs.2017.12.025
27. Chamanza R, Wright JA. A review of the comparative anatomy, histology, physiology and pathology of the nasal cavity of rats, mice, dogs and non-human primates. Relevance to inhalation toxicology and human health risk assessment. J Comp Pathol. 2015;153(4):287-314. DOI: 10.1016/j.jcpa.2015.08.009
28. Chari S, Sridhar K, Walenga R, Kleinstreuer C. Computational analysis of a 3D mucociliary clearance model predicting nasal drug uptake. J Aerosol Sci. 2021;155(5):105757. DOI: https://doi.org/10.1016/j.jaerosci.2021.105757
29. Escada PA, Lima C, da Silva JM. The human olfactory mucosa. Eur Arch Otorhinolaryngol. 2009;266(11):1675-1680. DOI: 10.1007/s00405-009-1073-x
30. Ladel S, Schlossbauer P, Flamm J, Luksch H, Mizaikoff B, Schindowski K. Improved in vitro model for intranasal mucosal drug delivery: Primary olfactory and respiratory epithelial cells compared with the permanent nasal cell line RPMI 2650. Pharmaceutics. 2019;11(8):367. DOI: 10.3390/pharmaceutics11080367
31. Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):614-628. DOI: 10.1016/j.addr.2011.11.002
32. Shrewsbury SB, Hocevar-Trnka J, Satterly KH, Craig KL, Lickliter JD, Hoekman J. The snap 101 double-blind, placebo/active-controlled, safety, pharmacokinetic, and pharmacodynamic study of inp105 (nasal olanzapine) in healthy adults. J Clin Psychiatry. 2020;81(4). DOI: 10.4088/JCP.19m13086
33. Cooper W, Ray S, Aurora SK, et al. Delivery of dihydroergotamine mesylate to the upper nasal space for the acute treatment of migraine: Technology in action. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2022; In Press.
34. Morgan KT, Jiang XZ, Patterson DL, Gross EA. The nasal mucociliary apparatus. Correlation of structure and function in the rat. Am Rev Respir Dis. 1984;130(2):275-281. DOI: 10.1164/arrd.1984.130.2.275
35. Silberstein SD, Shrewsbury SB, Hoekman J. Dihydroergotamine (dhe) — then and now: A narrative review. Headache. 2020;60(1):40-57. DOI: 10.1111/head.13700
36. Hoekman JD, Ho RJ. Effects of localized hydrophilic mannitol and hydrophobic Nelfinavir administration targeted to olfactory epithelium on brain distribution. AAPS PharmSciTech. 2011;12(2):534-543. DOI: 10.1208/s12249-011-9614-1
37. Darquenne C. Aerosol deposition in health and disease. J Aerosol Med Pulm Drug Deliv. 2012;25(3):140-147. DOI: 10.1089/jamp.2011.0916
38. Djupesland PG, Skretting A, Winderen M, Holand T. Breath actuated device improves delivery to target sites beyond the nasal valve. Laryngoscope. 2006;116(3):466-472. DOI: 10.1097/01.mlg.0000199741.08517.99
39. Onzetra® Xsail® [package insert]. Currax™ Pharmaceuticals LLC; 2019.
40. Shrewsbury SB, Jeleva M, Satterly KH, Lickliter J, Hoekman J. Stop 101: A phase 1, randomized, open-label, comparative bioavailability study of inp104, dihydroergotamine mesylate (dhe) administered intranasally by a I123 precision olfactory delivery (POD®) device, in healthy adult subjects. Headache. 2019;59(3):394-409. DOI: 10.1111/head.13476
41. Zeller SL, Citrome L. Managing agitation associated with schizophrenia and bipolar disorder in the emergency setting. West J Emerg Med. 2016;17(2):165-172. DOI: 10.5811/westjem.2015.12.28763
42. Dundar Y, Greenhalgh J, Richardson M, Dwan K. Pharmacological treatment of acute agitation associated with psychotic and bipolar disorder: A systematic review and meta-analysis. Hum Psychopharmacol. 2016;31(4):268-285. DOI: 10.1002/hup.2535
43. Klein LR, Driver BE, Miner JR, et al. Intramuscular midazolam, olanzapine, ziprasidone, or haloperidol for treating acute agitation in the emergency department. Ann Emerg Med. 2018;72(4):374-385. DOI: 10.1016/j.annemergmed.2018.04.027
44. Zyprexa [Prescribing information]. Indianapolis, In: Eli Lilly and Company; 2009.
45. Wilson MP, Pepper D, Currier GW, Holloman GH, Jr., Feifel D. The psychopharmacology of agitation: Consensus statement of the American Association For Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13(1):26-34. DOI: 10.5811/westjem.2011.9.6866
46. Battaglia J. Pharmacological management of acute agitation. Drugs. 2005;65(9):1207-1222. DOI: 10.2165/00003495-200565090-00003
47. Hanson LR, Fine JM, Svitak AL, Faltesek KA. Intranasal administration of CNS therapeutics to awake mice. J Vis Exp. 2013(74)4440. DOI: 10.3791/4440
48. Rouquier S, Blancher A, Giorgi D. The olfactory receptor gene repertoire in primates and mouse: Evidence for reduction of the functional fraction in primates. Proceedings of the National Academy of Sciences. 2000;97(6):2870-2874. DOI: 10.1073/pnas.040580197
49. Takahashi R. The formation of the human paranasal sinuses. Acta Otolaryngol Suppl. 1984;408:1-28. DOI: 10.3109/00016488409121162
50. Gajera B, Satterly KH, McKennon M, Muppaneni S, Wright J, Hoekman J. Formulation development and physicochemical characterization of a CNS drug product delivered intranasally by precision olfactory delivery (POD®) device technology. Presented at: American Association of Pharmaceutical Scientists Annual Meeting; November 4-7, 2018.
51. Brown V, Liu F. Intranasal delivery of a peptide with antidepressant-like effect. Neuropsychopharmacology. 2014;39(9):2131-2141. DOI: 10.1038/npp.2014.61
52. Harkema JR, Carey SA, Wagner JG. The nose revisited: A brief review of the comparative structure, function, and toxicologic pathology of the nasal epithelium. Toxicol Pathol. 2006;34(3):252-269. DOI: 10.1080/01926230600713475
53. Smith TR, Winner P, Aurora SK, Jeleva M, Hocevar-Trnka J, Shrewsbury SB. Stop 301: A phase 3, open-label study of safety, tolerability, and exploratory efficacy of inp104, precision olfactory delivery (POD®) of dihydroergotamine mesylate, over 24/52 weeks in acute treatment of migraine attacks in adult patients. Headache. 2021;61(8):1214-1226. DOI: 10.1111/head.14184
54. Trudhesa. [Prescribing information]. Manufactured in: Mipharm, S.p.A, Milano, Italy for Impel Neuropharma Inc., Seattle, WA. 2021.
55. Clinicaltrials.Gov. "INP105 proof-of-concept study for the acute treatment of agitation in adolescents with ASD (CALM 201)". NCT05163717 (https://clinicaltrials.Gov/ct2/show/nct05163717), accessed July 26, 2022.
2. Tang C, Prueksaritanont T. Use of in vivo animal models to assess pharmacokinetic drug-drug interactions. Pharm Res. 2010;27(9):1772-1787. DOI: 10.1007/s11095-010-0157-z
3. Yacobi A, Skelly JP, Shah VP, Benet LZ, eds. Integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. Springer; 1993.
4. Tuntland T, Ethell B, Kosaka T, et al. Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at novartis institute of biomedical research. Front Pharmacol. 2014;5:174. DOI: 10.3389/fphar.2014.00174
5. Price G, Patel DA. Drug bioavailability. In: Statpearls publishing. Treasure Island, FL 2020.
6. Jin JF, Zhu LL, Chen M, et al. The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection. Patient Prefer Adherence. 2015;9:923-942. DOI: 10.2147/PPA.S87271
7. Shrewsbury S, Hocevar-Trnka J, Hoekman J. Drug delivery via the upper nasal space: A novel route for anesthesiologists, intensivists and emergency department physicians? J Clin Anesth Intensive Care. 2021;2(1):8-14.
8. Djupesland PG, Messina JC, Mahmoud RA. Breath powered nasal delivery: A new route to rapid headache relief. Headache. 2013;53(Suppl 2):72-84. DOI: 10.1111/head.12186
9. Homayun B, Lin X, Choi HJ. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics. 2019;11(3):129. DOI: 10.3390/pharmaceutics11030129
10. Citrome L. Addressing the need for rapid treatment of agitation in schizophrenia and bipolar disorder: Focus on inhaled loxapine as an alternative to injectable agents. Therapeutics and clinical risk management. 2013;9:235-245. DOI: 10.2147/TCRM.S31484
11. Rech MA, Barbas B, Chaney W, Greenhalgh E, Turck C. When to pick the nose: Out-of-hospital and emergency department intranasal administration of medications. Ann Emerg Med. 2017;70(2):203-211. DOI: 10.1016/j.annemergmed.2017.02.015
12. Simonet C, Tolosa E, Camara A, Valldeoriola F. Emergencies and critical issues in parkinson’s disease. Pract Neurol. 2020;20(1):15-25. DOI: 10.1136/practneurol-2018-002075
13. Lipton RB, Munjal S, Buse DC, et al. Unmet acute treatment needs from the 2017 Migraine In America Symptoms And Treatment Study. Headache. 2019;59(8):1310-1323. DOI: 10.1111/head.13588
14. Detke HC, Millen BA, Zhang Q, et al. Rapid onset of effect of galcanezumab for the prevention of episodic migraine: Analysis of the evolve studies. Headache. 2020;60(2):348-359. DOI: 10.1111/head.13691
15. Rygg A, Hindle M, Longest PW. Absorption and clearance of pharmaceutical aerosols in the human nose: Effects of nasal spray suspension particle size and properties. Pharm Res. 2016;33(4):909-921. DOI: 10.1007/s11095-015-1837-5
16. Djupesland PG. Nasal drug delivery devices: Characteristics and performance in a clinical perspective-a review. Drug Deliv Transl Res. 2013;3(1):42-62. DOI: 10.1007/s13346-012-0108-9
17. Dhuria SV, Hanson LR, Frey WH, II. Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. J Pharm Sci. 2010;99(4):1654-1673. DOI: 10.1002/jps.21924
18. Mignani S, Shi X, Karpus A, Majoral JP. Non-invasive intranasal administration route directly to the brain using dendrimer nanoplatforms: An opportunity to develop new cns drugs. Eur J Med Chem. 2021;209:112905. DOI: 10.1016/j.ejmech.2020.112905
19. Kellerman DJ, Forst A, Combs DL, Borland S, Kori S. Assessment of the consistency of absorption of dihydroergotamine following oral inhalation: Pooled results from four clinical studies. J Aerosol Med Pulm Drug Deliv. 2013;26(5):297-306. DOI: 10.1089/jamp.2012.0999
20. Martin V, Hoekman J, Aurora SK, Shrewsbury SB. Nasal delivery of acute medications for migraine: The upper versus lower nasal space. J Clin Med. 2021;10(11)2468. DOI: 10.3390/jcm10112468
21. Musumeci T, Bonaccorso A, Puglisi G. Epilepsy disease and nose-to-brain delivery of polymeric nanoparticles: An overview. Pharmaceutics. 2019;11(3):118. DOI: 10.3390/pharmaceutics11030118
22. Miller JL, Ashford JW, Archer SM, Rudy AC, Wermeling DP. Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: A pilot pharmacokinetic study. Pharmacotherapy. 2008;28(7):875-882. DOI: 10.1592/phco.28.7.875
23. Hoekman J, Ray S, Aurora SK, Shrewsbury SB. The upper nasal space—a novel delivery route ideal for central nervous system drugs. US Neurol. 2020;16(1):25-31.
24. Gänger S, Schindowski K. Tailoring formulations for intranasal nose-to-brain delivery: A review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa. Pharmaceutics. 2018;10(3):116. DOI: 10.3390/pharmaceutics10030116
25. Djupesland PG, Messina JC, Mahmoud RA. The nasal approach to delivering treatment for brain diseases: An anatomic, physiologic, and delivery technology overview. Ther Deliv. 2014;5(6):709-733. DOI: 10.4155/tde.14.41
26. Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life Sci. 2018;195:44-52. DOI: 10.1016/j.lfs.2017.12.025
27. Chamanza R, Wright JA. A review of the comparative anatomy, histology, physiology and pathology of the nasal cavity of rats, mice, dogs and non-human primates. Relevance to inhalation toxicology and human health risk assessment. J Comp Pathol. 2015;153(4):287-314. DOI: 10.1016/j.jcpa.2015.08.009
28. Chari S, Sridhar K, Walenga R, Kleinstreuer C. Computational analysis of a 3D mucociliary clearance model predicting nasal drug uptake. J Aerosol Sci. 2021;155(5):105757. DOI: https://doi.org/10.1016/j.jaerosci.2021.105757
29. Escada PA, Lima C, da Silva JM. The human olfactory mucosa. Eur Arch Otorhinolaryngol. 2009;266(11):1675-1680. DOI: 10.1007/s00405-009-1073-x
30. Ladel S, Schlossbauer P, Flamm J, Luksch H, Mizaikoff B, Schindowski K. Improved in vitro model for intranasal mucosal drug delivery: Primary olfactory and respiratory epithelial cells compared with the permanent nasal cell line RPMI 2650. Pharmaceutics. 2019;11(8):367. DOI: 10.3390/pharmaceutics11080367
31. Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):614-628. DOI: 10.1016/j.addr.2011.11.002
32. Shrewsbury SB, Hocevar-Trnka J, Satterly KH, Craig KL, Lickliter JD, Hoekman J. The snap 101 double-blind, placebo/active-controlled, safety, pharmacokinetic, and pharmacodynamic study of inp105 (nasal olanzapine) in healthy adults. J Clin Psychiatry. 2020;81(4). DOI: 10.4088/JCP.19m13086
33. Cooper W, Ray S, Aurora SK, et al. Delivery of dihydroergotamine mesylate to the upper nasal space for the acute treatment of migraine: Technology in action. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2022; In Press.
34. Morgan KT, Jiang XZ, Patterson DL, Gross EA. The nasal mucociliary apparatus. Correlation of structure and function in the rat. Am Rev Respir Dis. 1984;130(2):275-281. DOI: 10.1164/arrd.1984.130.2.275
35. Silberstein SD, Shrewsbury SB, Hoekman J. Dihydroergotamine (dhe) — then and now: A narrative review. Headache. 2020;60(1):40-57. DOI: 10.1111/head.13700
36. Hoekman JD, Ho RJ. Effects of localized hydrophilic mannitol and hydrophobic Nelfinavir administration targeted to olfactory epithelium on brain distribution. AAPS PharmSciTech. 2011;12(2):534-543. DOI: 10.1208/s12249-011-9614-1
37. Darquenne C. Aerosol deposition in health and disease. J Aerosol Med Pulm Drug Deliv. 2012;25(3):140-147. DOI: 10.1089/jamp.2011.0916
38. Djupesland PG, Skretting A, Winderen M, Holand T. Breath actuated device improves delivery to target sites beyond the nasal valve. Laryngoscope. 2006;116(3):466-472. DOI: 10.1097/01.mlg.0000199741.08517.99
39. Onzetra® Xsail® [package insert]. Currax™ Pharmaceuticals LLC; 2019.
40. Shrewsbury SB, Jeleva M, Satterly KH, Lickliter J, Hoekman J. Stop 101: A phase 1, randomized, open-label, comparative bioavailability study of inp104, dihydroergotamine mesylate (dhe) administered intranasally by a I123 precision olfactory delivery (POD®) device, in healthy adult subjects. Headache. 2019;59(3):394-409. DOI: 10.1111/head.13476
41. Zeller SL, Citrome L. Managing agitation associated with schizophrenia and bipolar disorder in the emergency setting. West J Emerg Med. 2016;17(2):165-172. DOI: 10.5811/westjem.2015.12.28763
42. Dundar Y, Greenhalgh J, Richardson M, Dwan K. Pharmacological treatment of acute agitation associated with psychotic and bipolar disorder: A systematic review and meta-analysis. Hum Psychopharmacol. 2016;31(4):268-285. DOI: 10.1002/hup.2535
43. Klein LR, Driver BE, Miner JR, et al. Intramuscular midazolam, olanzapine, ziprasidone, or haloperidol for treating acute agitation in the emergency department. Ann Emerg Med. 2018;72(4):374-385. DOI: 10.1016/j.annemergmed.2018.04.027
44. Zyprexa [Prescribing information]. Indianapolis, In: Eli Lilly and Company; 2009.
45. Wilson MP, Pepper D, Currier GW, Holloman GH, Jr., Feifel D. The psychopharmacology of agitation: Consensus statement of the American Association For Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13(1):26-34. DOI: 10.5811/westjem.2011.9.6866
46. Battaglia J. Pharmacological management of acute agitation. Drugs. 2005;65(9):1207-1222. DOI: 10.2165/00003495-200565090-00003
47. Hanson LR, Fine JM, Svitak AL, Faltesek KA. Intranasal administration of CNS therapeutics to awake mice. J Vis Exp. 2013(74)4440. DOI: 10.3791/4440
48. Rouquier S, Blancher A, Giorgi D. The olfactory receptor gene repertoire in primates and mouse: Evidence for reduction of the functional fraction in primates. Proceedings of the National Academy of Sciences. 2000;97(6):2870-2874. DOI: 10.1073/pnas.040580197
49. Takahashi R. The formation of the human paranasal sinuses. Acta Otolaryngol Suppl. 1984;408:1-28. DOI: 10.3109/00016488409121162
50. Gajera B, Satterly KH, McKennon M, Muppaneni S, Wright J, Hoekman J. Formulation development and physicochemical characterization of a CNS drug product delivered intranasally by precision olfactory delivery (POD®) device technology. Presented at: American Association of Pharmaceutical Scientists Annual Meeting; November 4-7, 2018.
51. Brown V, Liu F. Intranasal delivery of a peptide with antidepressant-like effect. Neuropsychopharmacology. 2014;39(9):2131-2141. DOI: 10.1038/npp.2014.61
52. Harkema JR, Carey SA, Wagner JG. The nose revisited: A brief review of the comparative structure, function, and toxicologic pathology of the nasal epithelium. Toxicol Pathol. 2006;34(3):252-269. DOI: 10.1080/01926230600713475
53. Smith TR, Winner P, Aurora SK, Jeleva M, Hocevar-Trnka J, Shrewsbury SB. Stop 301: A phase 3, open-label study of safety, tolerability, and exploratory efficacy of inp104, precision olfactory delivery (POD®) of dihydroergotamine mesylate, over 24/52 weeks in acute treatment of migraine attacks in adult patients. Headache. 2021;61(8):1214-1226. DOI: 10.1111/head.14184
54. Trudhesa. [Prescribing information]. Manufactured in: Mipharm, S.p.A, Milano, Italy for Impel Neuropharma Inc., Seattle, WA. 2021.
55. Clinicaltrials.Gov. "INP105 proof-of-concept study for the acute treatment of agitation in adolescents with ASD (CALM 201)". NCT05163717 (https://clinicaltrials.Gov/ct2/show/nct05163717), accessed July 26, 2022.