Abstracts

Rationale: ZX008 is being developed as a low-dose adjunctive treatment for seizures in patients with Dravet syndrome (DS) and other pediatric-onset epilepsies. Most DS patients receive multiple antiepileptic drugs, making it challenging for caregivers to track correct administration times. This complexity increases with the potential for orally administered drugs to interact with food; for example, stiripentol must be taken with a meal but should not be taken with milk or dairy products. The present study was conducted to determine the effect on pharmacokinetics of administering ZX008 in the fasted or fed state. Methods: Healthy non-smoking subjects aged 18 to 50 years were enrolled in this open-label, crossover, Phase 1 pharmacokinetic study. Key exclusion criteria were the use of any medication known to induce or inhibit hepatic enzymes within the previous 30 days, history of alcohol or drug abuse, or a positive drug screen for illegal drugs or nonprescribed controlled substances. Subjects received a single dose of ZX008 (0.8 mg/kg) in a randomized order following a 10-hr overnight fast or 30 min after the start of consumption of a high-fat breakfast. A washout period of at least 9 days separated the 2 treatment periods. Venous blood samples were taken before each dose and periodically for 72 hours after each dose for determination of concentrations of fenfluramine and its metabolite, norfenfluramine. Plasma pharmacokinetic parameters were estimated for each subject by non-compartmental analysis with WinNonlin (v6.3 Phoenix Certara, USA). Results: A total of 14 subjects (5 were female; overall median age, 38 years [range: 20 to 44 years]; median body weight, 76.6 kg [range: 56.2 to 90.4 kg]) enrolled in the study, and 13 subjects completed both treatment periods (1 subject withdrew after the first treatment period due to a family emergency). The bioavailability of fenfluramine was similar in the fed and fasted states as shown by Cmax (adjusted geometric means 59.1 vs 56.7 ng/mL, respectively; ratio = 104.3%, 90% CI, 97.9 to 111.0 %) and AUC0-inf (adjusted geometric means 1640 vs 1600 ng•hr/mL; ratio = 102.7%, 90% CI, 98.9 to 106.7%). Similarly, no effect of food on exposure to norfenfluramine was observed. Seven subjects reported at least one treatment-emergent adverse event (TEAE) during the study, and all were mild in severity. The most commonly reported TEAEs were dizziness (n=3), headache (n=3), and somnolence (n=2). There was no notable food effect in the incidence of AEs, with a similar incidence reported following dosing with ZX008 in the fasted and fed state; 4 (28.6%) and 4 (30.8%) subjects reported 8 and 4 AEs, respectively. Conclusions: The similar bioavailability and tolerability of single 0.8 mg/kg oral doses of ZX008 in the fed and fasted state indicates that ZX008 may be administered without regard to meals. This provides caregivers with increased flexibility in their daily routine by not having to worry about timing of meals in relation to administration of ZX008. Funding: This study was funded by Zogenix, Inc.