Population Pharmacokinetics of Oral Baclofen in Pediatric Patients with聽Cerebral Palsy

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• 作者：Yang He ; PhD¹ ; Janice E. Brunstrom-Hernandez ; MD² ; Liu Lin Thio ; MD ; PhD² ; Shellie Lackey ; RN³ ; Deborah Gaebler-Spira ; MD⁴ ; ⁵ ; Maxine M. Kuroda ; PhD ; MPH⁵ ; Elaine Stashinko ; PhD ; RN⁶ ; Alexander H. Hoon Jr. ; MD ; MPH⁶ ; Jilda Vargus-Adams ; MD⁷ ; Richard D. Stevenson ; MD⁸ ; Stephanie Lowenhaupt ; RN ; CCRC⁹ ; John F. McLaughlin ; MD¹⁰ ; Ana Christensen ; MPH¹⁰ ; Nienke P. Dosa ; MD ; MPH¹¹ ; Maureen Butler ; BSN¹² ; Aloysia Schwabe ; MD¹³ ; Christina Lopez ; CCRP¹⁴ ; Desiree Roge ; MD¹⁵ ; Diane Kennedy ; RN ; PhD ; CCRC¹⁵ ; Ann Tilton ; MD¹⁶ ; Linda E. Krach ; MD¹⁷ ; Andrew Lewandowski ; PhD¹⁸ ; Hongying Dai ; PhD¹⁹ ; Andrea Gaedigk ; PhD²⁰ ; J. Steven Leeder ; PharmD ; PhD²⁰ ; William J. Jusko ; PhD¹ ; ^{wjjusko@buffalo.edu" class="auth_mail}
• 关键词：AUC蟿 ; 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
• 刊名：The Journal of Pediatrics
• 出版年：May, 2014
• 年：2014
• 卷：164
• 期：5
• 页码：1181-1188.e8
• 全文大小：2135 K

文摘

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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-聽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.