Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy.
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.
The Journal of pediatrics
Absorption; Administration, Oral; Adolescent; Baclofen; Body Weight; Cerebral Palsy; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Models, Statistical; Multivariate Analysis; Muscle Relaxants, Central
Absorption; Oral Administration; Baclofen; Body Weight; Cerebral Palsy; Drug Dose-Response Relationship; Drug Administration Schedule; Half-Life; Metabolic Clearance Rate
He, Y., Brunstrom-Hernandez, J., Thio, L., Lackey, S., Gaebler-Spira, D., Kuroda, M. M., Stashinko, E., Hoon, A. H., Vargus-Adams, J., Stevenson, R. D., Lowenhaupt, S., McLaughlin, J., Christensen, A., Dosa, N. P., Butler, M., Schwabe, A., Lopez, C., Roge, D., Kennedy, D., Tilton, A., Krach, L. E., Lewandowski, A., Dai, H., Gaedigk, A., Leeder, J. S., Jusko, W. J. Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy. The Journal of pediatrics 164, 1181-1188 (2014).