Alexis Arzimanoglou1, Jose A Ferreira2, Andrew Satlin3, Shannon Mendes4, Betsy Williams5, David Critchley6, Edgar Schuck7, Ziad Hussein8, Dinesh Kumar9, Shobha Dhadda10, Francesco Bibbiani11. 1. Epilepsy, Sleep and Paediatric Neurophysiology Department, University Hospitals of Lyon (HCL-HFME) and Lyon Neurosciences Research Center (CRNL), 59 Bld. Pinel, 60700 Lyon, France. Electronic address: aarzimanoglou@orange.fr. 2. Department of Pediatrics, University of South Florida, School of Medicine, Tampa, FL, USA; St. Joseph's Children's Hospital, Tampa, FL, USA; Pediatric Epilepsy and Neurology Specialists (PENS), 508 S. Habana Ave, Suite 340, Tampa, FL 33609, USA. Electronic address: jferreira@pensresearch.org. 3. Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: Andrew_Satlin@eisai.com. 4. Formerly of Eisai Inc., 100 Tice Boulevard, Woodcliff Lake, NJ, USA. Electronic address: other_medicine@yahoo.com. 5. Eisai Medical and Scientific Affairs, Eisai Inc., 100 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: Betsy_Williams@eisai.com. 6. Eisai Ltd., Hatfield, UK. Electronic address: David_Critchley@eisai.net. 7. Modelling and Simulation, Clinical Pharmacology, 155 Tice Boulevard, Eisai Inc., Woodcliff Lake, NJ 07677, USA. Electronic address: Edgar_Schuck@eisai.com. 8. Modelling and Simulation, Clinical Pharmacology, Eisai Ltd, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK. Electronic address: Ziad_Hussein@eisai.net. 9. Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: Dinesh_Kumar@eisai.com. 10. Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: Shobha_Dhadda@eisai.com. 11. Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: Francesco_Bibbiani@eisai.com.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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 concentrationsfrom 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. SIGNIFICANCE: 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. CLINICAL TRIAL REGISTRATION: Study 303 (clinicaltrials.gov: NCT01405053).
RCT Entities:
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. SIGNIFICANCE: 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. CLINICAL TRIAL REGISTRATION: Study 303 (clinicaltrials.gov: NCT01405053).