Population Pharmacokinetic Model of Dexmedetomidine in a Heterogeneous Group of Patients.
Adolescent
Adult
Age Factors
Aged
Aged, 80 and over
Body Weight
Child
Child, Preschool
Computer Simulation
Cytochrome P-450 CYP1A2
/ genetics
Dexmedetomidine
/ administration & dosage
Female
Humans
Hypnotics and Sedatives
/ administration & dosage
Infant
Infusions, Intravenous
Intensive Care Units
Male
Metabolic Clearance Rate
Middle Aged
Nonlinear Dynamics
Norepinephrine
/ therapeutic use
Polymorphism, Genetic
Young Adult
dexmedetomidine
intensive care unit
population pharmacokinetics
Journal
Journal of clinical pharmacology
ISSN: 1552-4604
Titre abrégé: J Clin Pharmacol
Pays: England
ID NLM: 0366372
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
06
04
2020
accepted:
28
04
2020
pubmed:
6
6
2020
medline:
13
8
2021
entrez:
6
6
2020
Statut:
ppublish
Résumé
Dexmedetomidine is a hepatically eliminated drug with sedative, anxiolytic, sympatholytic, and analgesic properties that has been increasingly used for various indications in the form of a short or continuous intravenous infusion. This study aimed to propose a population pharmacokinetic (PK) model of dexmedetomidine in a heterogeneous group of intensive care unit patients, incorporating 29 covariates potentially linked with dexmedetomidine PK. Data were collected from 70 patients aged between 0.25 and 88 years and treated with dexmedetomidine infusion for various durations at 1 of 4 medical centers. Statistical analysis was performed using a nonlinear mixed-effect model. Categorical and continuous covariates including demographic data, hemodynamic parameters, biochemical markers, and 11 single-nucleotide polymorphisms were tested. A 2-compartment model was used to describe dexmedetomidine PK. An allometric/isometric scaling was used to account for body weight difference in PK parameters, and the Hill equation was used to describe the maturation of clearance. Typical values of the central and peripheral volume of distribution and the systemic and distribution clearance for a theoretical adult patient were central volume of distribution = 22.50 L, peripheral volume of distribution = 86.1 L, systemic clearance = 34.7 L/h, and distribution clearance = 40.8 L/h. The CYP1A2 genetic polymorphism and noradrenaline administration were identified as significant covariates for clearance. A population PK model of dexmedetomidine was successfully developed. The proposed model is well calibrated to the observed data. The identified covariates account for <5% of interindividual variability and consequently are of low clinical significance for the purpose of dose adjustment.
Substances chimiques
Hypnotics and Sedatives
0
Dexmedetomidine
67VB76HONO
CYP1A2 protein, human
EC 1.14.14.1
Cytochrome P-450 CYP1A2
EC 1.14.14.1
Norepinephrine
X4W3ENH1CV
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1461-1473Informations de copyright
© 2020, The American College of Clinical Pharmacology.
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