A Single-Dose, Randomized, Open-Label, Parallel Design Study to Characterize the Pharmacokinetics of an Investigational Olanzapine Intranasal Spray Compared to a Reference Dose of Olanzapine Intramuscular Injection in Healthy Adult Males

Stuart Madden, PhD ; Leslie Citrome, MD, MPH ; Christoph U. Correll, MD, PhD ; Evelyn K. Shih, MD, PhD ; Miguel Lopez-Toledano, PhD ; Adrian L. Rabinowicz, MD ; Enrique Carrazana, MD

J Clin Psychiatry 2025;86(2):24m15665

Abstract

Objective: Injectable olanzapine for acute agitation in psychiatric disorders is limited to delivery by health care professionals in supervised settings. Intranasal (IN) administration offers a potential needle free route of delivery with favorable pharmacokinetics and patient experience, including the possibility of self-administration in community settings. Two IN formulations of olanzapine containing the permeation enhancer dodecyl maltoside (DDM) were assessed, with intramuscular (IM) olanzapine as a reference.

Methods: In this randomized phase 1 trial (conducted October 2023), healthy volunteers (N =24) were randomized 1:1: 1 to receive 1 dose of IN olanzapine 7.5 mg+0.25% DDM, IN olanzapine 7.5 mg+0.50% DDM, or olanzapine 7.5 mg IM. Plasma olanzapine concentrations were measured over time, and safety and tolerability were assessed.

Results: Mean peak plasma olanzapine concentrations were 31.5, 32.3, and 20.5 ng/mL for 0.25% and 0.50% DDM sprays and IM dosing, respectively. Median times to peak plasma concentration were 4.8, 10.2, and 37.8 minutes. After a single dose of the 0.25% and 0.50% DDM formulations, bioavailability was 88.8% and 83.3% of a single IM dose. All reported treatment emergent adverse events were mild, transient, and deemed possibly related to the study drug, with the most frequent being sedation (n = 24) and nasal discomfort lasting seconds (n = 16, IN treatments). Nasal irritation scores were grade 0 (no sign of nasal irritation or mucosal erosion), and suicide risk assessment was negative for all time points.

Conclusion: Two novel investigational IN formulations of olanzapine containing the permeation enhancer DDM showed favorable pharmacokinetics and an acceptable safety profile presenting no unexpected signals in healthy adults. Continued study is warranted.

Trial Registration: ClinicalTrials.gov identifier: NCT06600477.

J Clin Psychiatry 2025;86(2):24m15665

Author affiliations are listed at the end of this article.

Continue Reading...

Did you know members enjoy unlimited free PDF downloads as part of their subscription? Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.

Subscribe Now

Already a member? Login

Buy PDF for $40

Please sign in or purchase this PDF for $40.

References (39)

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5. American Psychiatric Publishing; 2013.
Citrome L, Correll CU, San L, et al. Alternative approaches for addressing acute agitation in schizophrenia and bipolar disorder. Prim Care Companion CNS Disord. 2024;26(1):23nr03596.
Roberts J, Gracia Canales A, Blanthorn-Hazell S, et al. Characterizing the experience of agitation in patients with bipolar disorder and schizophrenia. BMC Psychiatry. 2018;18(1):104. CrossRef
Garriga M, Pacchiarotti I, Kasper S, et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry. 2016;17(2):86–128. CrossRef
Fillit H, Aigbogun MS, Gagnon-Sanschagrin P, et al. Impact of agitation in long term care residents with dementia in the United States. Int J Geriatr Psychiatry. 2021;36(12):1959–1969.
Holloman GH Jr, Zeller SL. Overview of project BETA: best practices in evaluation and treatment of agitation. West J Emerg Med. 2012;13(1):1–2. CrossRef
Miner JR, Klein LR, Cole JB, et al. The characteristics and prevalence of agitation in an urban county emergency department. Ann Emerg Med. 2018;72(4):361–370. CrossRef
Correll CU, Yu X, Xiang Y, et al. Biological treatment of acute agitation or aggression with schizophrenia or bipolar disorder in the inpatient setting. Ann Clin Psychiatry. 2017;29(2):92–107.
Dhossche DM, Ghani SO. Who brings patients to the psychiatric emergency room? Psychosocial and psychiatric correlates. Gen Hosp Psychiatry. 1998;20(4):235–240.
Baldacara L, Ismael F, Leite V, et al. Brazilian guidelines for the management of psychomotor agitation. Part 1. Non-pharmacological approach. Braz J Psychiatry. 2019;41(2):153–167. CrossRef
Patel MX, Sethi FN, Barnes TR, et al. Joint BAP NAPICU evidence-based consensus guidelines for the clinical management of acute disturbance: de escalation and rapid tranquillisation. J Psychopharmacol. 2018;32(6):601–640. CrossRef
Faden J, Citrome L. Examining the safety, efficacy, and patient acceptability of inhaled loxapine for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. Neuropsychiatr Dis Treat. 2019;15:2273–2283. CrossRef
Chung S, Peters JM, Detyniecki K, et al. The nose has it: opportunities and challenges for intranasal drug administration for neurologic conditions including seizure clusters. Epilepsy Behav Rep. 2023;21:100581. CrossRef
Rabinowicz AL, Carrazana E, Maggio ET. Improvement of intranasal drug delivery with Intravail^®alkylsaccharide excipient as a mucosal absorption enhancer aiding in the treatment of conditions of the central nervous system. Drugs R D. 2021;21(4):361–369. CrossRef
VALTOCO^®(diazepam nasal spray). Full Prescribing Information. Neurelis Inc. 2023.
TOSYMRA^®(sumatriptan). Full Prescribing Information. Upsher-Smith Laboratories, LLC. 2021.
Neffy (epinephrine nasal spray). Full Prescribing Information. ARS Pharmaceuticals Operations, Inc. 2024.
Opvee (nalmefene nasal spray). Full Prescribing Information. Indivior Inc. 2023.
Maggio ET, Pillion DJ. High efficiency intranasal drug delivery using Intravail^®alkylsaccharide absorption enhancers. Drug Deliv Transl Res. 2013;3(1):16–25. CrossRef
Schoretsanitis G, Kane JM, Correll CU, et al. Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry. 2020;81(3):19cs13169.
Horvat M, Kadija M, Scavnicar A, et al. Association of smoking cigarettes, age, and sex with serum concentrations of olanzapine in patients with schizophrenia. Biochem Med (Zagreb). 2023;33(3):030702.
US Food and Drug Administration. Bioanalytical Method Validation Guidance for Industry. US Food and Drug Administration; 2018.
Agarwal SK, Kriel RL, Brundage RC, et al. A pilot study assessing the bioavailability and pharmacokinetics of diazepam after intranasal and intravenous administration in healthy volunteers. Epilepsy Res. 2013;105(3):362–367. CrossRef
Hogan RE, Gidal BE, Koplowitz B, et al. Bioavailability and safety of diazepam intranasal solution compared to oral and rectal diazepam in healthy volunteers. Epilepsia. 2020;61(3):455–464. CrossRef
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266–1277. CrossRef
Steinijans VW, Diletti E. Statistical analysis of bioavailability studies: parametric and nonparametric confidence intervals. Eur J Clin Pharmacol. 1983;24(1):127–136. CrossRef
Wheless JW, Miller I, Hogan RE, et al. Final results from a phase 3, long-term, open-label, repeat-dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy. Epilepsia. 2021;62(10):2485–2495. CrossRef
Vazquez B, Wheless J, Desai J, et al. Lack of observed impact of history or concomitant treatment of seasonal allergies or rhinitis on repeated doses of diazepam nasal spray administered per seizure episode in a day, safety, and tolerability: interim results from a phase 3, open-label, 12-month repeat-dose safety study. Epilepsy Behav. 2021;118:107898. CrossRef
Wright P, Birkett M, David SR, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158(7):1149–1151. CrossRef
Breier A, Meehan K, Birkett M, et al. A double-blind, placebo-controlled dose response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59(5):441–448. CrossRef
Meehan K, Zhang F, David S, et al. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol. 2001;21(4):389–397. CrossRef
Meehan KM, Wang H, David SR, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology. 2002;26(4):494–504.
San L, Marksteiner J, Zwanzger P, et al. State of acute agitation at psychiatric emergencies in Europe: the STAGE study. Clin Pract Epidemiol Ment Health. 2016;12:75–86. CrossRef
Bak M, Weltens I, Bervoets C, et al. The pharmacological management of agitated and aggressive behaviour: a systematic review and meta-analysis. Eur Psychiatry. 2019;57:78–100. CrossRef
Santilli N, Dewar S, Guerra C, et al. Use of intranasal rescue therapy for seizure clusters in students with epilepsy: nurses’ knowledge, perceptions, and practice. Epilepsy Behav Rep. 2023;22:100604. CrossRef
Penovich PE, Buelow J, Steinberg K, et al. Burden of seizure clusters on patients with epilepsy and caregivers: survey of patient, caregiver, and clinician perspectives. Neurologist. 2017;22(6):207–214.
Shrewsbury SB, Hocevar-Trnka J, Satterly KH, et al. 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):19m13086.
Bhanu C, Nimmons D, Petersen I, et al. Drug-induced orthostatic hypotension: a systematic review and meta-analysis of randomised controlled trials. PLoS Med. 2021;18(11):e1003821. CrossRef
Zyprexa (olanzapine). Full Prescribing Information. Lilly USA; 2021.