Esketamine inhaled as dry powder: Pharmacokinetic, pharmacodynamic and safety assessment in a preclinical study

Matłoka, Mikołaj; Janowska, Sylwia; Gajos-Draus, Anna; Ziółkowski, Hubert; Janicka, Monika; Perko, P.; Kamil, Kisło; Pankiewicz, Piotr; Moszczyński-Pętkowski, Rafał; Mach, Mateusz; Dera, Paulina; Abramski, Krzysztof; Teska-Kaminska, Malgorzata; Tratkiewicz, E.; Wieczorek, Maciej; Pieczykolan, Jerzy

doi:10.1016/j.pupt.2022.102127

Cited by 4 publications

(4 citation statements)

References 39 publications

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“…a therapy scheme for depression symptoms initiated with 56 mg and a maintenance phase for five weeks with a dose range of 56 or 84 mg. For Depressive Disorder and Major Depressive Disorder with Acute Suicidal Ideation or Behavior was incited with 84 mg intranasally two times a week for four weeks. [35][36][37] The most common side effects of ketamine seen in the studies were blurred vision, dizziness, fatigue, headache, nausea or vomiting, dry mouth, poor coordination, restlessness, anxiety, irritability, constipation, nightmare occurrence, and headache. However, the transient dissociative effect is the most common of the side effects.…”

Section: Discussionmentioning

confidence: 99%

“…34 Must recently, the esketamine, the S-enantiomer of ketamine, was demonstrated good results by intranasal administrations, with a therapy scheme for depression symptoms initiated with 56 mg and a maintenance phase for five weeks with a dose range of 56 or 84 mg. For Depressive Disorder and Major Depressive Disorder with Acute Suicidal Ideation or Behavior was incited with 84 mg intranasally two times a week for four weeks. 35–37…”

Section: Discussionmentioning

confidence: 99%

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Evidence for the beneficial effect of ketamine in the treatment of patients with post-traumatic stress disorder: A systematic review and meta-analysis

Albuquerque

Macedo

Delmondes

et al. 2022

J Cereb Blood Flow Metab

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Post-traumatic stress disorder (PTSD) is an anxiety disorder with manifestations somatic resulting from reliving the trauma. The therapy for the treatment of PTSD has limitations, between reduced efficacy and “PTSD pharmacotherapeutic crisis”. Scientific evidence has shown that the use of ketamine has benefits for the treatment of depressive disorders and other symptoms present in PTSD compared to other conventional therapies. Therefore, this study aims to analyze the available evidence on the effect of ketamine in the treatment of post-traumatic stress. The systematic review and the meta-analysis were conducted following PRISMA guidelines and RevManager software, using randomized controlled trials and eligible studies of quality criteria for data extraction and analysis. The sample design evaluated included the last ten years, whose search resulted in 594 articles. After applying the exclusion criteria, 35 articles were selected, of which 14 articles were part of the sample, however, only six articles were selected the meta-analysis. The results showed that the ketamine is a promising drug in the management of PTSD with effect more evident performed after 24 h evaluated by MADRS scale. However, the main limitations of the present review demonstrate that more high-quality studies are needed to investigate the influence of therapy, safety, and efficacy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evidence for the beneficial effect of ketamine in the treatment of patients with post-traumatic stress disorder: A systematic review and meta-analysis

Albuquerque

Macedo

Delmondes

et al. 2022

J Cereb Blood Flow Metab

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“…Although the relative antidepressant effects of esketamine and noresketamine remain unclear, there are indications that oral esketamine may be less effective for TRD than intranasal or intravenous esketamine administration, 23–25 potentially due to a relatively lower exposure to esketamine. In accordance, a recent study in 34 patients with TRD found a positive association between a higher esketamine concentration and treatment response but no correlation between the noresketamine concentration and treatment response 26 .…”

Section: Discussionmentioning

confidence: 99%

Increasing the bioavailability of oral esketamine by a single dose of cobicistat: A case study

Vos,

Hemminga,

Aarnoutse

et al. 2024

Pharmacotherapy

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BackgroundIntranasal esketamine is an approved drug for treatment‐resistant depression (TRD); however, it is costly and may result in specific adverse effects. In this single case study, we explored if oral esketamine can be a suitable alternative.MethodsIn collaboration with a 39‐year‐old female with TRD, we compared plasma concentration curves of intranasal (84 mg) and oral (1, 2 and 4 mg/kg) esketamine. Because oral esketamine has a relatively low bioavailability, it results in a different ratio between esketamine and its primary metabolite noresketamine. To increase the bioavailability of oral esketamine, we co‐administered a single dose of the cytochrome P‐450 (CYP) 3A4 inhibitor cobicistat (150 mg).ResultsFor all doses administered, oral esketamine resulted in lower esketamine but higher noresketamine peak plasma concentrations compared with intranasal treatment. Using oral esketamine it was not possible to generate a similar esketamine plasma concentration curve as with the intranasal treatment, except when combined with cobicistat (esketamine 2 mg/kg plus cobicistat 150 mg).ConclusionsOur findings demonstrate that cobicistat effectively increases the bioavailability of oral esketamine. Further research is required in a larger population, especially to investigate the clinical benefit of cobicistat as a booster drug for oral esketamine.

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“…Intramuscular effects are slower (with 93% bioavailability), followed by intranasal (with 8–45% bioavailability) and oral effects (with 17–29% availability) (Li & Vlisides, 2016). Ketamine inhaled in powder form has a good safety profile in clinical settings (Matłoka et al, 2022), but given that most recreational use (e.g., in nightclubs) appears to be use in powder form, such nasal use can increase the risk of adverse effects given the contexts of use and higher likelihood of people using a less pure product (He et al, 2020; Palamar et al, 2019). The US FDA has also reported concerns about some nasal sprays (which can be obtained now in clinics), particularly take-home nasal sprays, as these appear to increase risk for misuse, “abuse,” and adverse effects (US FDA, 2022).…”

Section: Discussionmentioning

confidence: 99%

Characteristics of poisonings involving ketamine in the United States, 2019–2021

et al. 2022

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Background: The use of ketamine, a controlled dissociative anesthetic, has become more widespread in recent years with recreational/nonmedical use increasing and ketamine becoming more widely available in clinics to treat depression. Aims: We examined recent trends in adverse effects related to ketamine use. Methods: US National Poison Control data were examined, focusing on ketamine exposures among those aged ⩾13 between 2019 and 2021 ( n = 758). We examined quarterly trends in exposure and delineated correlates of patients experiencing a major adverse effect or death. Results: The number of reported exposures increased 81.1% from 2019 Quarter 1 through 2021 Quarter 4, from 37 to 67 ( p = 0.018). The majority of patients were male (57.1%), and the plurality of cases involved intentional misuse or “abuse” (39.5%), followed by suspected suicide attempt (19.7%) and unintentional exposure (18.9%). A fifth (19.6%) experienced a major adverse effect or death. A third (33.4%) co-used other drugs; the drugs most commonly co-used were benzodiazepines (14.6%), alcohol (10.3%), and opioids (8.7%). Co-use of gamma-hydroxybutyrate (GHB; adjusted prevalence ratio (aPR) = 3.43, 95% confidence interval (CI): 1.57–7.46) and opioids (aPR = 2.44, 95% CI: 1.46–4.08) was associated with increased risk for a major adverse effect or death, as was injection-only administration (aPR = 2.68, 95% CI: 1.21–5.92). Conclusions: Although still rare, poisonings involving ketamine have increased in recent years. Polydrug use—particularly with opioids or GHB—appears to be a particular risk factor for more serious adverse effects. As prevalence of use increases, it is important to monitor adverse effects and co-occurring behaviors to inform timely prevention and harm reduction as needed.

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Esketamine inhaled as dry powder: Pharmacokinetic, pharmacodynamic and safety assessment in a preclinical study

Cited by 4 publications

References 39 publications

Evidence for the beneficial effect of ketamine in the treatment of patients with post-traumatic stress disorder: A systematic review and meta-analysis

Evidence for the beneficial effect of ketamine in the treatment of patients with post-traumatic stress disorder: A systematic review and meta-analysis

Increasing the bioavailability of oral esketamine by a single dose of cobicistat: A case study

Characteristics of poisonings involving ketamine in the United States, 2019–2021

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