Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression

Pérez-Ruixo, Carlos; Rossenu, Stefaan; Zannikos, Peter; Nandy, Partha; Singh, Jaskaran; Drevets, Wayne C.; Pérez-Ruixo, Juan José

doi:10.1007/s40262-020-00953-4

Cited by 36 publications

(52 citation statements)

References 37 publications

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“…This pattern, along with delayed formation of N3G, may indicate that the formation of N3G was due to the uptake of naloxone through the oral route after initial nasal administration due drugs being transported from the nasal cavity to the pharynx, oesophagus and stomach. The involvement of such an oral component from swallowed drug in metabolism has recently been shown for nasally administered esketamine [ 21 ]. The nasal bioavailability of naloxone is approximately 50%, and the rest of the nasal naloxone is not accounted for.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the increased bioavailability of naloxone after nasal administration during remifentanil infusion may be explained by a higher oral bioavailability of swallowed naloxone due to reduction of the pre-systemic metabolism of naloxone by remifentanil. For nasal esketamine it was shown that a decrease in hepatic blood flow gave an increase in AUC and Cmax of esketamine [ 21 ]. Reduced portal blood flow is a common effect of many sedative drugs [ 23 ], and could be the explanation of a potential interaction between remifentanil and nasal naloxone.…”

Section: Discussionmentioning

confidence: 99%

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The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers

Tylleskär

Skarra

Skulberg

et al. 2021

Eur J Clin Pharmacol

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Purpose Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. Methods We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide (N3G), the main metabolite of naloxone, with or without exposure to remifentanil. To enable direct comparison of the three studies, the data are presented as metabolic ratios (ratio of metabolite to mother substance, N3G/naloxone) and dose-corrected values of the area under the curve and maximum concentration (Cmax). Results Under remifentanil exposure, the time to maximum concentration (Tmax) for N3G was significantly higher for intranasal administration of 71 min compared to intramuscular administration of 40 min. The dose-corrected Cmax of N3G after intranasal administration of naloxone under remifentanil exposure was significantly lower (4.5 ng/mL) than in subjects not exposed to remifentanil (7.8–8.4 ng/mL). The metabolic ratios after intranasal administration rose quickly after 30–90 min and were 2–3 times higher at 360 min compared to intravenous and intramuscular administration. Remifentanil exposure resulted in a much slower increase of the N3G/naloxone ratio after intranasal administration compared to intranasal administration with the absence of remifentanil. After remifentanil infusion was discontinued, this effect gradually diminished. From 240 min there was no significant difference between the ratios observed after intranasal naloxone administration. Conclusion Remifentanil increases the bioavailability of naloxone after nasal administration by reducing the pre-systemic metabolism of the swallowed part of the nasal dose.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers

Tylleskär

Skarra

Skulberg

et al. 2021

Eur J Clin Pharmacol

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“…CYP2B6 is among other enzymes (CYP2C9, CYP3A4) involved in the hepatic N-demethylation of ketamine to norketamine (Yanagihara et al, 2001 ; Hijazi and Boulieu, 2002 ; Portmann et al, 2010 ; Desta et al, 2012 ; Palacharla et al, 2018 ). Although ketamine has a large therapeutic window, its use is limited due to low efficacy and huge interindividaul variability in treatment response including ADRs that require cessation of therapy (Kvarnström et al, 2004 ; Noppers et al, 2010 ; Laskowski et al, 2011 ; Hardy et al, 2012 ; Perez-Ruixo et al, 2020 ). Ketamine has been associated with increased blood pressure, alteration of speech, muscular discoordination, euphoria, hallucination, loss of consciousness, seizure, nausea, out of body experience, hypothermia, traffic accident or drowning and irrational behavior (Iyalomhe and Iyalomhe, 2014 ; Lonnée et al, 2018 ; Gajewski et al, 2020 ).…”

Section: Population Disparity In the Use Of Cyp2b6 Substrates And Consequent Exposure To Substrate-specific Adverse Drug Reaction (Adr)mentioning

confidence: 99%

CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations—Implication for Drug Safety, Dosing, and Individualized Therapy

et al. 2021

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Adverse drug reactions (ADRs) are one of the major causes of morbidity and mortality worldwide. It is well-known that individual genetic make-up is one of the causative factors of ADRs. Approximately 14 million single nucleotide polymorphisms (SNPs) are distributed throughout the entire human genome and every patient has a distinct genetic make-up which influences their response to drug therapy. Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of antiretroviral, antimalarial, anticancer, and antidepressant drugs. These drug classes are commonly in use worldwide and face specific population variability in side effects and dosing. Parts of this variability may be caused by single nucleotide polymorphisms (SNPs) in the CYP2B6 gene that are associated with altered protein expression and catalytic function. Population variability in the CYP2B6 gene leads to changes in drug metabolism which may result in adverse drug reactions or therapeutic failure. So far more than 30 non-synonymous variants in CYP2B6 gene have been reported. The occurrence of these variants show intra and interpopulation variability, thus affecting drug efficacy at individual and population level. Differences in disease conditions and affordability of drug therapy further explain why some individuals or populations are more exposed to CYP2B6 pharmacogenomics associated ADRs than others. Variabilities in drug efficacy associated with the pharmacogenomics of CYP2B6 have been reported in various populations. The aim of this review is to highlight reports from various ethnicities that emphasize on the relationship between CYP2B6 pharmacogenomics variability and the occurrence of adverse drug reactions. In vitro and in vivo studies evaluating the catalytic activity of CYP2B6 variants using various substrates will also be discussed. While implementation of pharmacogenomic testing for personalized drug therapy has made big progress, less data on pharmacogenetics of drug safety has been gained in terms of CYP2B6 substrates. Therefore, reviewing the existing evidence on population variability in CYP2B6 and ADR risk profiles suggests that, in addition to other factors, the knowledge on pharmacogenomics of CYP2B6 in patient treatment may be useful for the development of personalized medicine with regards to genotype-based prescription.

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“…Esketaminas, ketamino S-enantiomeras − tai N-metild-aspartato receptorių antagonistas, kuris, vartojamas antidepresanto dozių (mažų dozių) intervale, laikinai padidina glutamaterginį signalo perdavimą, dėl kurio įvyksta α-amino-3-hidroksi-5-metil-4 -izoksazolepropiono rūgšties receptorių aktyvacija . Esketamino nosies purškalas (Spravato ™) buvo patvirtintas naudoti kartu su geriamuoju antidepresantu, gydant gydymui atsparią depresiją JAV, Europoje ir daugelyje kitų šalių [16].…”

Section: Tyrimo Rezultataiunclassified

Esketaminas Ir Gydymui Atspari Depresija

Grigas¹

2021

Health Sciences

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Tyrimo tikslas. Apžvelgti ir apibendrinti įrodymais grįstos medicinos duomenis apie esketamino naudingumą ir pritaikymą gydyti gydymui atsparią depresiją. Apžvelgti medikamento farmakologinį veikimo mechanizmą, klinikinį naudingumą bei pateikti klinikines medikamento skyrimo rekomendacijas, siekiant užtikrinti tinkamą bei saugų preparato vartojimą. Metodika. Atlikta teminių mokslinių straipsnių paieška Pubmed, SpringerLink duomenų bazėse, naudojant reikšminius žodžius: didysis depresinis sutrikimas, gydymui atspari depresija, esketaminas. Iš daugiau nei 70 mokslinių publikacijų atrinkta 30 straipsnių. Rezultatai. Įvardinta gydymui atsparios depresijos problematika. Apžvelgtas atsparios depresijos gydymui vartojamo medikamento esketamino veikimo mechanizmas, klinikinis naudingumas bei pateiktos klinikinės rekomendacijos specialistams, medicininėje praktikoje skiriantiems esketaminą rezistentiškos depresijos gydymui. Išvados. Esketaminas, vartojamas kartu su kitu, naujai paskirtu SSRI ar SNRI grupės geriamuoju antidepresantu, yra efektyvus preparatas, tinkamas gydyti gydymui atsparią depresiją. Ankstesnės terapijos metu, skiriant gydymą bent dviem skirtingais antidepresantais, tinkamomis dozėmis ir pakankamą gydymo laiką, depresijos simptomai nesumažėjo. Pacientams, vartojantiems esketaminą, stebima mažesnė depresijos recidyvo rizika. Esketaminas mažina gydymui atsparia depresija sergančių pacientų savižudybės riziką. Medikamentas vartojamas sveikatos specialisto priežiūroje. Po preparato inhaliacijos pacientas stebimas 2 valandas ir vertinama, ar nepasireiškia ankstyvieji, po medikamento pavartojimo atsiradandantys nepageidaujami reiškiniai: arterinė hipertenzija, disociaciniai (konversiniai) sutrikimai bei sedacinis poveikis. Užtikrinus tinkamą ankstyvųjų nepageidaujamų reiškinių kontrolę ir paciento stebėseną, esketaminas yra saugus preparatas gydyti gydymui atsparią depresiją.

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Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression

Cited by 36 publications

References 37 publications

The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers

The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers

CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations—Implication for Drug Safety, Dosing, and Individualized Therapy

Esketaminas Ir Gydymui Atspari Depresija

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