title: Mechanism-based population pharmacokinetic and pharmacodynamic modeling of intravenous and intranasal dexmedetomidine in healthy subjects.
abstract: OBJECTIVE
  Dexmedetomidine is an α2-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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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 50 values) than cardiovascular effects of dexmedetomidine.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 404 Kapoor Hall, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
authors.forename: Heedoo
authors.initials: H
authors.lastname: Yoo
authors.affiliation: Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, FI-20521, Turku, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Iirola
authors.affiliation: Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, FI-20521, Turku, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Vilo
authors.affiliation: Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, FI-20521, Turku, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Manner
authors.affiliation: Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, FI-20521, Turku, Finland.
authors.forename: Riku
authors.initials: R
authors.lastname: Aantaa
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Unit of Clinical Pharmacology, TYKSLAB, FI-20520, Turku, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Lahtinen
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Unit of Clinical Pharmacology, TYKSLAB, FI-20520, Turku, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, PO Box 340, FI-00029 HUS, Helsinki, Finland.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 404 Kapoor Hall, State University of New York at Buffalo, Buffalo, NY, 14214, USA. wjjusko@buffalo.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000281:Administration, Intranasal; D001682:Biological Availability; D001794:Blood Pressure; D018592:Cross-Over Studies; D020927:Dexmedetomidine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000378:metabolism; D006339:Heart Rate; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D009638:Norepinephrine / Q000378:metabolism; D064232:Visual Analog Scale; D055815:Young Adult
chemical_list: D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine; D009638:Norepinephrine; D004837:Epinephrine
keywords: Dexmedetomidine; Mechanism-based modeling; Norepinephrine; Pharmacodynamics; Population pharmacokinetics; α2-adrenoceptor agonist