Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy

Yang He, Janice E. Brunstrom-Hernandez, Liu Lin Thio, Shellie Lackey, Deborah J 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 Tilton & 6 others Linda E. Krach, Andrew Lewandowski, Hongying Dai, Andrea Gaedigk, J. Steven Leeder, William J. Jusko

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
JournalJournal of Pediatrics
Volume164
Issue number5
DOIs
StatePublished - Jan 1 2014

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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
  • 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

Cite this

He, Yang ; Brunstrom-Hernandez, Janice E. ; Thio, Liu Lin ; Lackey, Shellie ; Gaebler-Spira, Deborah J ; Kuroda, Maxine M. ; Stashinko, Elaine ; Hoon, Alexander H. ; 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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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, 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",
author = "Yang He and Brunstrom-Hernandez, {Janice E.} and Thio, {Liu Lin} and Shellie Lackey and Gaebler-Spira, {Deborah J} and Kuroda, {Maxine M.} and Elaine Stashinko and Hoon, {Alexander H.} 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",
month = "1",
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doi = "10.1016/j.jpeds.2014.01.029",
language = "English (US)",
volume = "164",
journal = "Journal of Pediatrics",
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He, Y, Brunstrom-Hernandez, JE, Thio, LL, Lackey, S, Gaebler-Spira, DJ, 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

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 J; Kuroda, Maxine M.; Stashinko, Elaine; Hoon, Alexander H.; 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, 01.01.2014.

Research output: Contribution to journalArticle

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 J

AU - Kuroda, Maxine M.

AU - Stashinko, Elaine

AU - Hoon, Alexander H.

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 - 2014/1/1

Y1 - 2014/1/1

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 - AUCτ

KW - Area under the curve within the dosing interval

KW - BS

KW - Body weight in kg

KW - Bootstrap

KW - CL

KW - CP

KW - Cerebral palsy

KW - Clearance

KW - Creatinine clearance

KW - GAGE

KW - GERD

KW - Gastroesophageal reflux disease

KW - Gestational age

KW - IIV

KW - Inter-individual variability

KW - MTT

KW - Mean transit time

KW - NCA

KW - Noncompartmental analysis

KW - PG

KW - PK

KW - Pharmacogenomics

KW - Pharmacokinetics

KW - PopPK

KW - Population pharmacokinetics

KW - QID

KW - SNP

KW - SVPC

KW - Single-nucleotide polymorphism

KW - Standardized visual predictive check

KW - TDOS

KW - TID

KW - Total daily dose

KW - WTKG

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U2 - 10.1016/j.jpeds.2014.01.029

DO - 10.1016/j.jpeds.2014.01.029

M3 - Article

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JO - Journal of Pediatrics

T2 - Journal of Pediatrics

JF - Journal of Pediatrics

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