Abstracts

Rationale: An oral solution of fenfluramine (ZX008) is under development as a low-dose adjunctive treatment of seizures in patients with Dravet syndrome (DS) and other pediatric-onset epilepsies. Current DS treatment uses combinations of antiepileptics such as stiripentol, clobazam, valproate, topiramate, and levetiracetam, and thus assessing potential drug-drug interactions when adding any new agent to DS treatment regimens is clinically important. We assessed the pharmacokinetics (PK) and safety of ZX008 administered with and without stiripentol, clobazam, and valproate (“combination regimen”), and the PK of stiripentol, clobazam, and valproate administered with and without ZX008. Methods: This study had an open-label, randomized, single-dose, 3-period crossover design. Twenty-six healthy adult subjects were randomized to the following treatment regimens over 3 periods: A: Single dose ZX008 0.8 mg/kg; B: stiripentol 3500 mg/clobazam 20 mg/valproate 25 mg/kg; C: ZX008 0.8 mg/kg plus stiripentol 3500 mg/clobazam 20 mg/valproate 25 mg/kg. The maximum dose of valproate was 1500 mg, regardless of subject weight. Periods were separated by 17 days. Blood samples were obtained intensively for 72 hours after drug administration. PK parameters were calculated using non-compartmental methods. Results: The average age of participants was 34.5 years (range 21-50), 58% were female, and 89% Caucasian. ZX008 did not have any significant impact on any of the PK profiles in the combination regimen (stiripentol, clobazam, and valproate). The combination regimen had a moderate effect on fenfluramine PK. The 3-drug combination increased the geometric mean Cmax, AUC(0-t), and AUC(0-inf) of fenfluramine by 1.2-, 1.7-, and 1.7-fold, respectively, while reducing the AUC(0-t) of norfenfluramine by 41%. There was no obvious effect of CYP2D6 genotype status on fenfluramine or norfenfluramine PK. Average numbers of adverse events (AEs) per subject reported for treatment regimens A, B, and C were 1.8, 1.5, and 2.6, respectively. All AEs were mild to moderate in intensity and resolved spontaneously. Conclusions: The combination regimen of stiripentol/clobazam/valproate had a moderate impact on the PK of fenfluramine and norfenfluramine. ZX008 did not have any significant impact on the combination regimen PK. Co-administration of this combination regimen with ZX008 did not significantly impact the number and severity of AEs reported. The impact of this combination regimen on the PK of ZX008 in patients is being further evaluated using a PBPK modeling approach and will be confirmed by ongoing Phase 3 clinical trials Funding: This study was funded by Zogenix, Inc.