Mechanism-based population pharmacokinetic and pharmacodynamic modeling of intravenous and intranasal dexmedetomidine in healthy subjects.
Purpose: Dexmedetomidine is an α-adrenoceptor agonist used for perioperative and intensive care sedation. This study develops mechanism-based population pharmacokinetic-pharmacodynamic models for the cardiovascular and central nervous system (CNS) effects of intravenously (IV) and intranasally (IN)...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 71; no. 10; pp. 1197 - 1208 |
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| Autores principales: | , , , , , , , , |
| Formato: | equations & formulas research tables/charts randomized controlled trial Journal Article |
| Publicado: |
Springer Nature
Oct2015
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=109345390&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 109345390 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Oct2015 vid: 71 iid: 10 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 109345390 109345390 109345390 10.1007/s00228-015-1913-0 109345390 ppf: 1197 ppct: 11 formats: fmt: @attributes: type: P tig: atl: Mechanism-based population pharmacokinetic and pharmacodynamic modeling of intravenous and intranasal dexmedetomidine in healthy subjects. aug: au: Yoo, Heedoo Iirola, Timo Vilo, Sanna Manner, Tuula Aantaa, Riku Lahtinen, Maria Scheinin, Mika Olkkola, Klaus Jusko, William affil: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 404 Kapoor Hall, State University of New York at Buffalo, Buffalo 14214 USA sug: subj: Imidazoles Pharmacokinetics Imidazoles Pharmacodynamics Imidazoles Administration and Dosage Administration, Intravenous Hypnotics and Sedatives Administration and Dosage Human Male Imidazoles Blood Norepinephrine Blood Epinephrine Blood Biological Availability Descriptive Statistics Cardiovascular System Drug Effects Central Nervous System Drug Effects Secondary Analysis Adolescence Young Adult Data Analysis Software Randomized Controlled Trials Crossover Design Hemodynamics Visual Analog Scaling Funding Source Adolescent: 13-18 years Male ab: Purpose: Dexmedetomidine is an α-adrenoceptor agonist used for perioperative and intensive care sedation. This study develops mechanism-based population pharmacokinetic-pharmacodynamic models for the cardiovascular and central nervous system (CNS) effects of intravenously (IV) and intranasally (IN) administered dexmedetomidine in healthy subjects. Method: Single doses of 84 μg of dexmedetomidine were given once IV and once IN to six healthy men. Plasma dexmedetomidine concentrations were measured for 10 h along with plasma concentrations of norepinephrine (NE) and epinephrine (E). Blood pressure, heart rate, and CNS drug effects (three visual analog scales and bispectral index) were monitored to assess the pharmacological effects of dexmedetomidine. PK-PD modeling was performed for recently published data (Eur J Clin Pharmacol 67: 825, 2011). Results: Pharmacokinetic profiles for both IV and IN doses of dexmedetomidine were well fitted using a two-compartment PK model. Intranasal bioavailability was 82 %. Dexmedetomidine inhibited the release of NE and E to induce their decline in blood. This decrease in NE was captured with an indirect response model. The concentrations of the mediator NE served via a biophase/transduction step and nonlinear pharmacologic functions to produce reductions in blood pressure and heart rate, while a direct effect model was used for the CNS effects. Conclusion: The comprehensive panel of two biomarkers and seven response measures were well captured by the population PK/PD models. The subjects were more sensitive to the CNS (lower EC values) than cardiovascular effects of dexmedetomidine. pubtype: Academic Journal doctype: equations & formulas research tables/charts randomized controlled trial Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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