Aloysia Schwabe

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.

Botulinum Toxin in the Treatment of Pediatric Upper Limb Spasticity.

Botulinum neurotoxin (BoNT) is one of the mainstays in the treatment of pediatric spasticity and dystonia. When considering initiation of BoNT treatment for spasticity, treatment goals and responses to prior conservative measures such as passive range of motion exercises, splinting, and other medication trials should be reviewed. As a general rule, children should be engaged in therapy services around the time of the injections and have a robust home program in place. When managing spasticity in children with BoNT injections, the practitioner should be well versed in functional anatomy with specialized training in injection techniques. Localization techniques in addition to anatomical landmarks are recommended for improved efficacy and include limited electromyography, electrical stimulation, and/or ultrasound guidance. A follow-up visit for the purpose of reassessment during the peak effect of the drug is advised. It is known that BoNT is effective at reducing spasticity and improving range of motion, but it remains to be determined to what degree this translates into improved function, activity, and participation.

Temporal Gait Measures Associated With Overground and Treadmill Walking in Rett Syndrome

Rett syndrome is a severe neurodevelopmental disorder leading to intellectual impairment and global developmental delays, including difficulty or inability to walk. Assessing differences in temporal parameters and associated variability between overground and treadmill walking is important if gait training is to be incorporated into intervention protocols. Fourteen female patients with Rett syndrome (mean age 10.4 years ± SD 5.1) were evaluated during overground and treadmill walking. Stride, stance, swing, and double support times, and the variance of these measures, were obtained. Wilcoxon signed-rank tests were used to assess for potential differences between overground and treadmill measures. Treadmill gait resulted in decreases in swing and double support times. When normalized to stride time, treadmill gait displayed an increase in stance time with decreases in swing and double support times. Excepting stance time, treadmill gait resulted in decreased variability, indicating a more regularized gait while walking on the treadmill. These results suggest that treadmill walking can be beneficial for ambulatory patients with Rett syndrome and could be incorporated into a therapeutic protocol designed to maintain the maximum degree of mobility and overall general health as part of a comprehensive health management approach.

Current clinical evidence does not support a link between TBL1XR1 and Rett syndrome: Description of one patient with Rett features and a novel mutation in TBL1XR1, and a review of TBL1XR1 phenotypes.

Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas Texas Children’s Hospital, Jan and Dan Duncan Neurological Research Institute, Houston, Texas Department of Neurology, Baylor College of Medicine, Houston, Texas Department of Pediatrics, Baylor College of Medicine, Houston, Texas Texas Children’s Hospital, Houston, Texas Departments of Pediatrics and Pathology, Stanford University, Stanford, California Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas