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 Holliday 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

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)
JournalJournal of Pediatrics
Volume164
Issue number5
DOIs
StatePublished - 2014

Fingerprint

Baclofen
Cerebral Palsy
Pharmacokinetics
Pediatrics
Population
Body Weight
Maximum Tolerated Dose
Age Factors
Sex Characteristics
Half-Life
Linear Models

Keywords

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

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

He, Y., Brunstrom-Hernandez, J. E., Thio, L. L., Lackey, S., Gaebler-Spira, D., Kuroda, M. M., ... Jusko, W. J. (2014). Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy. Journal of Pediatrics, 164(5). https://doi.org/10.1016/j.jpeds.2014.01.029

Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy. / He, Yang; Brunstrom-Hernandez, Janice E.; Thio, Liu Lin; Lackey, Shellie; Gaebler-Spira, Deborah; Kuroda, Maxine M.; Stashinko, Elaine; Hoon, Alexander Holliday; Vargus-Adams, Jilda; Stevenson, Richard D.; Lowenhaupt, Stephanie; McLaughlin, John F.; Christensen, Ana; Dosa, Nienke P.; Butler, Maureen; Schwabe, Aloysia; Lopez, Christina; Roge, Desiree; Kennedy, Diane; Tilton, Ann; Krach, Linda E.; Lewandowski, Andrew; Dai, Hongying; Gaedigk, Andrea; Leeder, J. Steven; Jusko, William J.

In: Journal of Pediatrics, Vol. 164, No. 5, 2014.

Research output: Contribution to journalArticle

He, Y, Brunstrom-Hernandez, JE, Thio, LL, Lackey, S, Gaebler-Spira, D, Kuroda, MM, Stashinko, E, Hoon, AH, Vargus-Adams, J, Stevenson, RD, Lowenhaupt, S, McLaughlin, JF, Christensen, A, Dosa, NP, Butler, M, Schwabe, A, Lopez, C, Roge, D, Kennedy, D, Tilton, A, Krach, LE, Lewandowski, A, Dai, H, Gaedigk, A, Leeder, JS & Jusko, WJ 2014, 'Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy', Journal of Pediatrics, vol. 164, no. 5. https://doi.org/10.1016/j.jpeds.2014.01.029
He Y, Brunstrom-Hernandez JE, Thio LL, Lackey S, Gaebler-Spira D, Kuroda MM et al. Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy. Journal of Pediatrics. 2014;164(5). https://doi.org/10.1016/j.jpeds.2014.01.029
He, Yang ; Brunstrom-Hernandez, Janice E. ; Thio, Liu Lin ; Lackey, Shellie ; Gaebler-Spira, Deborah ; Kuroda, Maxine M. ; Stashinko, Elaine ; Hoon, Alexander Holliday ; Vargus-Adams, Jilda ; Stevenson, Richard D. ; Lowenhaupt, Stephanie ; McLaughlin, John F. ; Christensen, Ana ; Dosa, Nienke P. ; Butler, Maureen ; Schwabe, Aloysia ; Lopez, Christina ; Roge, Desiree ; Kennedy, Diane ; Tilton, Ann ; Krach, Linda E. ; Lewandowski, Andrew ; Dai, Hongying ; Gaedigk, Andrea ; Leeder, J. Steven ; Jusko, William J. / Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy. In: Journal of Pediatrics. 2014 ; Vol. 164, No. 5.
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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. 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.",
keywords = "3 times a day, 4 times a day, Area under the curve within the dosing interval, AUCτ, Body weight in kg, Bootstrap, BS, Cerebral palsy, CL, Clearance, CP, Creatinine clearance, GAGE, Gastroesophageal reflux disease, GERD, Gestational age, IIV, Inter-individual variability, Mean transit time, MTT, NCA, Noncompartmental analysis, PG, Pharmacogenomics, Pharmacokinetics, PK, PopPK, Population pharmacokinetics, QID, Single-nucleotide polymorphism, SNP, Standardized visual predictive check, SVPC, TDOS, TID, Total daily dose, WTKG",
author = "Yang He and Brunstrom-Hernandez, {Janice E.} and Thio, {Liu Lin} and Shellie Lackey and Deborah Gaebler-Spira and Kuroda, {Maxine M.} and Elaine Stashinko and Hoon, {Alexander Holliday} and Jilda Vargus-Adams and Stevenson, {Richard D.} and Stephanie Lowenhaupt and McLaughlin, {John F.} and Ana Christensen and Dosa, {Nienke P.} and Maureen Butler and Aloysia Schwabe and Christina Lopez and Desiree Roge and Diane Kennedy and Ann Tilton and Krach, {Linda E.} and Andrew Lewandowski and Hongying Dai and Andrea Gaedigk and Leeder, {J. Steven} and Jusko, {William J.}",
year = "2014",
doi = "10.1016/j.jpeds.2014.01.029",
language = "English (US)",
volume = "164",
journal = "Journal of Pediatrics",
issn = "0022-3476",
publisher = "Mosby Inc.",
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TY - JOUR

T1 - Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy

AU - He, Yang

AU - Brunstrom-Hernandez, Janice E.

AU - Thio, Liu Lin

AU - Lackey, Shellie

AU - Gaebler-Spira, Deborah

AU - Kuroda, Maxine M.

AU - Stashinko, Elaine

AU - Hoon, Alexander Holliday

AU - Vargus-Adams, Jilda

AU - Stevenson, Richard D.

AU - Lowenhaupt, Stephanie

AU - McLaughlin, John F.

AU - Christensen, Ana

AU - Dosa, Nienke P.

AU - Butler, Maureen

AU - Schwabe, Aloysia

AU - Lopez, Christina

AU - Roge, Desiree

AU - Kennedy, Diane

AU - Tilton, Ann

AU - Krach, Linda E.

AU - Lewandowski, Andrew

AU - Dai, Hongying

AU - Gaedigk, Andrea

AU - Leeder, J. Steven

AU - Jusko, William J.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - 3 times a day

KW - 4 times a day

KW - Area under the curve within the dosing interval

KW - AUCτ

KW - Body weight in kg

KW - Bootstrap

KW - BS

KW - Cerebral palsy

KW - CL

KW - Clearance

KW - CP

KW - Creatinine clearance

KW - GAGE

KW - Gastroesophageal reflux disease

KW - GERD

KW - Gestational age

KW - IIV

KW - Inter-individual variability

KW - Mean transit time

KW - MTT

KW - NCA

KW - Noncompartmental analysis

KW - PG

KW - Pharmacogenomics

KW - Pharmacokinetics

KW - PK

KW - PopPK

KW - Population pharmacokinetics

KW - QID

KW - Single-nucleotide polymorphism

KW - SNP

KW - Standardized visual predictive check

KW - SVPC

KW - TDOS

KW - TID

KW - Total daily dose

KW - WTKG

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