title: Clonidine clearance matures rapidly during the early postnatal period: a population pharmacokinetic analysis in newborns with neonatal abstinence syndrome.
abstract: The population pharmacokinetic (PK) profile of oral clonidine was characterized in newborns with neonatal abstinence syndrome, and significant covariates affecting its PK parameters were identified. Plasma clonidine concentration data were obtained from a clinical trial in which 36 newborns, aged 1 to 25 days (postnatal age, PNA) and weighing 2.1 to 3.9 kg, were enrolled to take multiple oral doses of clonidine. The population PK model of clonidine was developed by NONMEM, and significant covariates were identified, followed by nonparametric bootstraps (2000 replicates) and simulation experiments. A 1-compartment open linear PK model was chosen to describe plasma concentrations of clonidine, and body weight and PNA were significant covariates for apparent clearance (CL/F) as follows: CL/F (L/h) = 15.2 × [body weight (kg)/70](0.75) × [PNA (day)(0.441)/(4.06(0.441) + PNA (day)(0.441))]. Furthermore, CL/F of clonidine increased rapidly with PNA during the first month of life after body weight was adjusted. Any optimal dosage regimen for clonidine in term neonates should be based on infant's age and body weight, and 1.5 µg/kg every 4 hours is proposed starting the second week of life based on the simulation results.
authors.affiliation: Center for Drug Development Science, Department of Bio-pharmaceutical Sciences, School of Pharmacy, University of California San Francisco, San Francisco, California, USA.
authors.forename: Hong-Guang
authors.initials: HG
authors.lastname: Xie
authors.forename: Ying Jun
authors.initials: YJ
authors.lastname: Cao
authors.forename: Estelle B
authors.initials: EB
authors.lastname: Gauda
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Agthe
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.forename: Howard
authors.initials: H
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003000:Clonidine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D006801:Humans; D007231:Infant, Newborn; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009357:Neonatal Abstinence Syndrome / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D010919:Placebos; D011446:Prospective Studies
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D010919:Placebos; D003000:Clonidine