Safety and pharmacokinetic profile of rufinamide in pediatric patients aged less than 4 years with Lennox-Gastaut syndrome: An interim analysis from a multicenter, randomized, active-controlled, open-label study

• Published in: European journal of paediatric neurology Vol. 20; no. 3; pp. 393 - 402
• Main Authors: Arzimanoglou, Alexis, Ferreira, Jose A., Satlin, Andrew, Mendes, Shannon, Williams, Betsy, Critchley, David, Schuck, Edgar, Hussein, Ziad, Kumar, Dinesh, Dhadda, Shobha, Bibbiani, Francesco
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2016
• Subjects: Anticonvulsants - adverse effects; Anticonvulsants - pharmacokinetics; Antiepileptic drug therapy; Child, Preschool; Female; Humans; Infant; Infants; Lennox Gastaut Syndrome - drug therapy; Lennox-Gastaut syndrome; Male; Neurology; Pediatrics; Pharmacokinetic; Randomized study; Rufinamide; safety; Triazoles - adverse effects; Triazoles - pharmacokinetics; AED; Rufinamide; Antiepileptic drug therapy; MedDRA; CI; EEG; CRCL; ECG; Infants; Pharmacokinetic; AUC; SD; Lennox-Gastaut syndrome; TEAE; safety; SAE; IIV; Cav; LGS; Randomized study; PK; CL/F; antiepileptic drug; steady-state exposure; interindividual variability; treatment-emergent adverse event; Medical Dictionary for Regulatory Activities; electrocardiogram; serious adverse event; creatinine clearance; C av; electroencephalogram; area under the concentration–time curve; confidence interval; apparent clearance; standard deviation
• ISSN: 1090-3798; 1532-2130
• DOI: 10.1016/j.ejpn.2015.12.015

A good knowledge of safety and age group-specific pharmacokinetics (PK) of antiepileptic drugs (AEDs) in young pediatric patients is of great importance in clinical practice. This paper presents 6-month interim safety and PK from an ongoing 2-year open-label study (Study 303) of adjunctive rufinamide treatment in pediatric subjects ≥1 to <4 years with inadequately controlled epilepsies of the Lennox-Gastaut syndrome (LGS) spectrum. Subjects (N = 37) were randomized to either rufinamide or any other approved AED chosen by the investigator as adjunctive therapy to the subject's existing regimen of 1–3 AEDs. Interim safety results showed that treatment-emergent adverse events (TEAEs) were similar between the rufinamide (22 [88.0%]) and any-other-AED group (9 [81.8%]), with most events considered mild or moderate. A population PK analysis was conducted including plasma rufinamide concentrations from Study 303 and two other study populations of LGS subjects ≥4 years. The rufinamide PK profile was dose independent. The apparent clearance (CL/F) estimated from the PK model was 2.19 L/h; it was found to increase significantly as a function of body weight. Coadministration of valproic acid significantly decreased rufinamide CL/F. CL/F was not significantly affected by other concomitant AEDs, age, gender, race, hepatic function, or renal function. No adjustments to body weight-based rufinamide dosing in subjects ≥1 to <4 years are necessary. Rufinamide was safe and well tolerated in these pediatric subjects. Results from the interim analysis demonstrate that rufinamide's safety and PK profile is comparable in subjects ≥1 to <4 and ≥4 years with LGS. Study 303 (clinicaltrials.gov: NCT01405053). •Study 303 features an active comparator arm with investigator-chosen add-on AEDs.•Rufinamide was safe and well tolerated in pediatric subjects ≥1 to <4 y of age.•Rufinamide PK in subjects ≥1 to <4 y comparable to prior analyses in LGS subjects ≥4 y.•No adjustments necessary to weight-based dosing for rufinamide in patients ≥1 to <4 y.