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 (V ss/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.
      AUCτ ( Area under the curve within the dosing interval), BS ( Bootstrap), CL ( Clearance), CLCR ( Creatinine clearance), CP ( Cerebral palsy), GAGE ( Gestational age), GERD ( Gastroesophageal reflux disease), IIV ( Inter-individual variability), MTT ( Mean transit time), NCA ( Noncompartmental analysis), PG ( Pharmacogenomics), PK ( Pharmacokinetics), PopPK ( Population pharmacokinetics), SNP ( Single-nucleotide polymorphism), SVPC ( Standardized visual predictive check), QID ( 4 times a day), TID ( 3 times a day), TDOS ( Total daily dose), WTKG ( Body weight in kg)
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