A phase I, randomized, open-label, single-dose, 3-period crossover study to evaluate the drug-drug interaction between ZX008 (fenfluramine HCl oral solution) and a
regimen of stiripentol, clobazam, and valproate in healthy subjects
Brooks Boyd, Steven Smith, Arnold Gammaitoni, Bradley S. Galer, Gail M. Farfel
Zogenix, Inc., Emeryville, CA, USA
DOI 10.5414/CP203276
Abstract
Objective: Phase I, open-label, randomized, single-dose, 3-period crossover study assessing pharmacokinetics (PK) and safety of ZX008, a liquid oral formulation of fenfluramine (FFA) under development for adjunctive treatment of Dravet syndrome and Lennox-Gastaut syndrome, administered with and without a combined antiepileptic drug (AED) regimen of stiripentol (STP), valproate (VPA), and clobazam (CLB) (STP regimen). Materials and methods: 26 healthy adults were administered the following treatments: ZX008 0.8 mg/kg; STP 3,500 mg, CLB 20 mg, VPA 25 mg/kg (max. 1,500 mg); and ZX008 0.8 mg/kg + STP regimen. Dose periods were 17 days apart. Blood samples were obtained for 72 hours after drug administration and used to calculate non-compartmental PK parameters. Results: Statistical bioequivalence-type analysis demonstrated ZX008 had no significant impact on the PK of any drug in the STP regimen, while the STP regimen moderately affected FFA PK. The 3-drug combination increased the geometric mean C<sub>max</sub>, AUC<sub>0–t</sub>, and AUC<sub>0–inf</sub> of FFA while reducing the C<sub>max</sub> and AUC<sub>0–t</sub> of its major metabolite, norfenfluramine (norFFA). Adverse events (AEs) were mild to moderate and resolved spontaneously. ZX008 + STP regimen co-administration to healthy adult subjects modestly impacted the number but not severity of AEs. Conclusion: Results show that the STP regimen had a moderate impact on FFA and norFFA PK and ZX008 had no significant impact on the 3 STP regimen drugs. ZX008 would not be expected to alter the clinical response of patients to this regimen by means of an effect on PK. When administering these drugs together, a downward dose adjustment of ZX008 may be warranted.
Author Details
Authors
Departments
- Zogenix, Inc., Emeryville, CA, USA
Address
Brooks Boyd, PhD
, Vice President
Development, Zogenix, Inc.
5858 Horton Street, Suite 455
Emeryville, CA 94608, USA
Email:
[email protected]
Citation
Brooks Boyd, Steven Smith, Arnold Gammaitoni, Bradley S. Galer, and Gail M. Farfel.A phase I, randomized, open-label, single-dose, 3-period crossover study to evaluate the drug-drug interaction between ZX008 (fenfluramine HCl oral solution) and a
regimen of stiripentol, clobazam, and valproate in healthy subjects
. 2019; 57: 11-19. doi: 10.5414/CP203276.
