Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy

Yang He, Janice E. Brunstrom-Hernandez, Liu Lin Thio, Shellie Lackey, Deborah Gaebler-Spira, Maxine M. Kuroda, Elaine Stashinko, Alexander H. Hoon, Jilda Vargus-Adams, Richard D. Stevenson, Stephanie Lowenhaupt, John F. McLaughlin, Ana Christensen, Nienke P. Dosa, Maureen Butler, Aloysia Schwabe, Christina Lopez, Desiree Roge, Diane Kennedy, Ann TiltonLinda E. Krach, Andrew Lewandowski, Hongying Dai, Andrea Gaedigk, J. Steven Leeder, William J. Jusko

Research output: Contribution to journalArticle

14 Scopus citations

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. Subjects design 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. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)1181-1188.e8
JournalJournal of Pediatrics
Volume164
Issue number5
DOIs
StatePublished - 2014

Keywords

  • 3 times a day
  • 4 times a day
  • AUCτ
  • Area under the curve within the dosing interval
  • BS
  • Body weight in kg
  • Bootstrap
  • CL
  • CP
  • Cerebral palsy
  • Clearance
  • Creatinine clearance
  • GAGE
  • GERD
  • Gastroesophageal reflux disease
  • Gestational age
  • IIV
  • Inter-individual variability
  • MTT
  • Mean transit time
  • NCA
  • Noncompartmental analysis
  • PG
  • PK
  • Pharmacogenomics
  • Pharmacokinetics
  • PopPK
  • Population pharmacokinetics
  • QID
  • SNP
  • SVPC
  • Single-nucleotide polymorphism
  • Standardized visual predictive check
  • TDOS
  • TID
  • Total daily dose
  • WTKG

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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    He, Y., Brunstrom-Hernandez, J. E., Thio, L. L., Lackey, S., Gaebler-Spira, D., Kuroda, M. M., Stashinko, E., Hoon, A. H., Vargus-Adams, J., Stevenson, R. D., Lowenhaupt, S., McLaughlin, J. F., Christensen, A., Dosa, N. P., Butler, M., Schwabe, A., Lopez, C., Roge, D., Kennedy, D., ... Jusko, W. J. (2014). Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy. Journal of Pediatrics, 164(5), 1181-1188.e8. https://doi.org/10.1016/j.jpeds.2014.01.029