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 Jr, 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, Linda E Krach, Andrew Lewandowski, Hongying Dai, Andrea Gaedigk, J Steven Leeder, William J Jusko, Yang He, Janice E Brunstrom-Hernandez, Liu Lin Thio, Shellie Lackey, Deborah Gaebler-Spira, Maxine M Kuroda, Elaine Stashinko, Alexander H Hoon Jr, 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, Linda E Krach, Andrew Lewandowski, Hongying Dai, Andrea Gaedigk, J Steven Leeder, William J Jusko

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.

Trial registration: ClinicalTrials.gov NCT00607542.

Copyright © 2014 Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Subject screening and disposition chart.
Figure 2
Figure 2
Schematic model structure of baclofen PK. A 2-compartment model was constructed with a first-order absorption rate constant (ka) and first-order clearance. The delayed absorption process was described by a number (n) of chained transit steps with a first-order transit rate constant (ktr). Ac and Ap are the amounts of drug in central (Vc) and peripheral (Vp) compartments, CLD represents distributional clearance between the two compartments, and F denotes bioavailability.
Figure 3
Figure 3
The measured R- and S-baclofen concentrations versus time after the last dose for all subjects. The data were stratified according to Daily Dose, TDOSs.
Figure 4
Figure 4
Correlation plots of AUCt and Cmax for R- versus S-baclofen. Open circles are AUCt or Cmax values; solid lines are linear regression line for correlation; dashed lines are identity lines.
Figure 5
Figure 5
The relationships of observed AUCt versus TDOS per kg body weight for R- (top) and S-(bottom) baclofen. Solid lines are regression lines.
Figure 6
Figure 6
Model fitting plots for representative individuals in different dose groups.
Figure 7
Figure 7
Correlation matrix plots for IIV (Eta) of Bayesian parameter estimations (CL, Vc, ka, MTT, and N) versus possible covariates WTKG, AGE in years, GAGE in weeks, TDOS in mg, disease severity (GMFC), and CLCR. Solid lines are the Loess regression lines.
Figure 8
Figure 8
Relationship between R-baclofen clearance and age. A, Apparent clearance corrected for body weight in kg (CL/WTKG). B, Clearance corrected for the power coefficient of weight (CL/BWT0.529). Open symbols are the subjects with ABCC9 rs11046232 heterozygous AT genotypes and solid symbols are subjects with TT homozygous genotypes. The linear regression line depicts subjects with TT homozygous genotypes (r2 = 0.459, panel A; r2 = 0.001, panel B).
Figure 9
Figure 9
A, Goodness-of-fit plots for R-baclofen PK data, individual model predictions (top) and population model predictions (bottom) versus observed data points. Solid lines are identity lines. B, Conditional weighted residuals (CWRES) versus time after last dose (top) or model predictions (bottom; PRED, population prediction). Solid lines are reference lines (y = 0).
Figure 10
Figure 10
SVPC plots for combined R- and S-baclofen PK data. Solid lines are model predicted medians; dashed lines are 5th (upper) and 95th (lower) percentiles.

Source: PubMed

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