title: Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy.
abstract: OBJECTIVE
  To characterize the population pharmacokinetics (PK) of oral baclofen and assess impact of patient-specific covariates in children with cerebral palsy (CP) in order to support its clinical use.
  Children (2-17 years of age) with CP received a dose of titrated oral baclofen from 2.5 mg 3 times a day to a maximum tolerated dose of up to 20 mg 4 times a day. PK sampling followed titration of 10-12 weeks. Serial R- and S-baclofen plasma concentrations were measured for up to 16 hours in 49 subjects. Population PK modeling was performed using NONMEM 7.1 (ICON PLC; Ellicott City, Maryland).
  
  
  RESULTS
  R- and S-baclofen showed identical concentration-time profiles. Both baclofen enantiomers exhibited linear and dose/kg-proportional PK, and no sex differences were observed. Average baclofen terminal half-life was 4.5 hours. A 2-compartment PK model with linear elimination and transit absorption steps adequately described concentration-time profiles of both baclofen enantiomers. The mean population estimate of apparent clearance/F was 0.273 L/h/kg with 33.4% inter-individual variability (IIV), and the apparent volume of distribution (Vss/F) was 1.16 L/kg with 43.9% IIV. Delayed absorption was expressed by a mean transit time of 0.389 hours with 83.7% IIV. Body weight, a possible genetic factor, and age were determinants of apparent clearance in these children.
  
  
  CONCLUSIONS
  The PK of oral baclofen exhibited dose-proportionality and were adequately described by a 2-compartment model. Our population PK findings suggest that baclofen dosage can be based on body weight (2 mg/kg per day) and the current baclofen dose escalation strategy is appropriate in the treatment of children with CP older than 2 years of age.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo SUNY, Buffalo, NY.
authors.forename: Yang
authors.initials: Y
authors.lastname: He
authors.affiliation: Pediatric Neurology Cerebral Palsy Center and Departments of Neurology and Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, MO.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Brunstrom-Hernandez
authors.affiliation: Pediatric Neurology Cerebral Palsy Center and Departments of Neurology and Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, MO.
authors.forename: Liu Lin
authors.initials: LL
authors.lastname: Thio
authors.affiliation: Department of Urology, St. Louis Children's Hospital, St. Louis, MO.
authors.forename: Shellie
authors.initials: S
authors.lastname: Lackey
authors.affiliation: Rehabilitation Institute of Chicago, Feinberg School of Medicine at Northwestern University, Chicago, IL; Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine at Northwestern University, Chicago, IL.
authors.forename: Deborah
authors.initials: D
authors.lastname: Gaebler-Spira
authors.affiliation: Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine at Northwestern University, Chicago, IL.
authors.forename: Maxine M
authors.initials: MM
authors.lastname: Kuroda
authors.affiliation: Department of Neurology and Developmental Medicine, Kennedy Krieger Institute and Johns Hopkins University, Baltimore, MD.
authors.forename: Elaine
authors.initials: E
authors.lastname: Stashinko
authors.affiliation: Department of Neurology and Developmental Medicine, Kennedy Krieger Institute and Johns Hopkins University, Baltimore, MD.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Hoon
authors.affiliation: Division of Pediatric Rehabilitation, Cincinnati Children's Hospital Medical Center, and Center for Epidemiology and Biostatistics, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Jilda
authors.initials: J
authors.lastname: Vargus-Adams
authors.affiliation: Department of Pediatrics-Developmental Pediatrics, University of Virginia School of Medicine, Charlottesville, VA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Stevenson
authors.affiliation: Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lowenhaupt
authors.affiliation: Department of Pediatrics Developmental Medicine, Seattle Children's Hospital, Seattle, WA.
authors.forename: John F
authors.initials: JF
authors.lastname: McLaughlin
authors.affiliation: Department of Pediatrics Developmental Medicine, Seattle Children's Hospital, Seattle, WA.
authors.forename: Ana
authors.initials: A
authors.lastname: Christensen
authors.affiliation: Center for Development, Behavior, and Genetics, SUNY Upstate Medical University, Syracuse, NY.
authors.forename: Nienke P
authors.initials: NP
authors.lastname: Dosa
authors.affiliation: Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY.
authors.forename: Maureen
authors.initials: M
authors.lastname: Butler
authors.affiliation: Department of Physical Medicine and Rehabilitation, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
authors.forename: Aloysia
authors.initials: A
authors.lastname: Schwabe
authors.affiliation: Department of Pediatric Neurology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
authors.forename: Christina
authors.initials: C
authors.lastname: Lopez
authors.affiliation: Department of Rehabilitation Medicine, Children's Mercy Hospital, Kansas City, MO.
authors.forename: Desiree
authors.initials: D
authors.lastname: Roge
authors.affiliation: Department of Rehabilitation Medicine, Children's Mercy Hospital, Kansas City, MO.
authors.forename: Diane
authors.initials: D
authors.lastname: Kennedy
authors.affiliation: Department of Neurology and Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Ann
authors.initials: A
authors.lastname: Tilton
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, MN.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Krach
authors.affiliation: The EMMES Corporation, Rockville, MD.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lewandowski
authors.affiliation: Department of Medical Research, Children's Mercy Hospitals and Clinics, Kansas City, MO.
authors.forename: Hongying
authors.initials: H
authors.lastname: Dai
authors.affiliation: Division of Clinical Pharmacology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.affiliation: Division of Clinical Pharmacology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO.
authors.forename: J Steven
authors.initials: JS
authors.lastname: Leeder
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo SUNY, Buffalo, NY. Electronic address: wjjusko@buffalo.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000293:Adolescent; D001418:Baclofen / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001835:Body Weight; D002547:Cerebral Palsy / Q000097:blood / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D015233:Models, Statistical; D015999:Multivariate Analysis; D009125:Muscle Relaxants, Central / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D009125:Muscle Relaxants, Central; D001418:Baclofen