Yang He1, Janice E Brunstrom-Hernandez2, Liu Lin Thio2, Shellie Lackey3, Deborah Gaebler-Spira4, Maxine M Kuroda5, Elaine Stashinko6, Alexander H Hoon6, Jilda Vargus-Adams7, Richard D Stevenson8, Stephanie Lowenhaupt9, John F McLaughlin10, Ana Christensen10, Nienke P Dosa11, Maureen Butler12, Aloysia Schwabe13, Christina Lopez14, Desiree Roge15, Diane Kennedy15, Ann Tilton16, Linda E Krach17, Andrew Lewandowski18, Hongying Dai19, Andrea Gaedigk20, J Steven Leeder20, William J Jusko21. 1. Department of Pharmaceutical Sciences, University at Buffalo SUNY, Buffalo, NY. 2. 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. 3. Department of Urology, St. Louis Children's Hospital, St. Louis, MO. 4. 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. 5. Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine at Northwestern University, Chicago, IL. 6. Department of Neurology and Developmental Medicine, Kennedy Krieger Institute and Johns Hopkins University, Baltimore, MD. 7. Division of Pediatric Rehabilitation, Cincinnati Children's Hospital Medical Center, and Center for Epidemiology and Biostatistics, University of Cincinnati College of Medicine, Cincinnati, OH. 8. Department of Pediatrics-Developmental Pediatrics, University of Virginia School of Medicine, Charlottesville, VA. 9. Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA. 10. Department of Pediatrics Developmental Medicine, Seattle Children's Hospital, Seattle, WA. 11. Center for Development, Behavior, and Genetics, SUNY Upstate Medical University, Syracuse, NY. 12. Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY. 13. Department of Physical Medicine and Rehabilitation, Baylor College of Medicine and Texas Children's Hospital, Houston, TX. 14. Department of Pediatric Neurology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX. 15. Department of Rehabilitation Medicine, Children's Mercy Hospital, Kansas City, MO. 16. Department of Neurology and Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA. 17. Department of Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, MN. 18. The EMMES Corporation, Rockville, MD. 19. Department of Medical Research, Children's Mercy Hospitals and Clinics, Kansas City, MO. 20. Division of Clinical Pharmacology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO. 21. Department of Pharmaceutical Sciences, University at Buffalo SUNY, Buffalo, NY. Electronic address: wjjusko@buffalo.edu.
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.
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.
Authors: Ellen B Fung; Lisa Samson-Fang; Virginia A Stallings; Mark Conaway; Gregory Liptak; Richard C Henderson; Gordon Worley; Maureen O'Donnell; Randy Calvert; Peter Rosenbaum; William Chumlea; Richard D Stevenson Journal: J Am Diet Assoc Date: 2002-03
Authors: H E Wiersma; C J van Boxtel; J J Butter; W M C van Aalderen; T Omari; M A Benninga Journal: Ther Drug Monit Date: 2003-02 Impact factor: 3.681
Authors: Matthew J McLaughlin; Yang He; Janice Brunstrom-Hernandez; Liu Lin Thio; Bruce C Carleton; Colin J D Ross; Andrea Gaedigk; Andrew Lewandowski; Hongying Dai; William J Jusko; J Steven Leeder Journal: PM R Date: 2017-09-01 Impact factor: 2.298