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 Cmax, AUC0–t, and AUC0–inf of FFA while reducing the Cmax and AUC0–t 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.
Highlights
Fenfluramine (FFA) has been shown to be effective in open-label studies for the treatment of Dravet syndrome (DS), a severe form of childhood epilepsy known as severe myoclonic epilepsy of infancy, or SMEI [2]
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
STP acts by inhibiting cytochrome P450 enzymes, indirectly increasing the concentration of other antiepileptic drug (AED) metabolized by those enzymes [13]
Summary
Fenfluramine (FFA) has been shown to be effective in open-label studies for the treatment of Dravet syndrome (DS), a severe form of childhood epilepsy known as severe myoclonic epilepsy of infancy, or SMEI [2]. In patients 1 – 29 years of age with DS, low-dose FFA (0.12 – 1.0 mg/kg/day) has produced prolonged reduction in seizure frequency [3, 4, 5]. Low-dose FFA has shown preliminary beneficial results in reducing seizure frequency in another form of pharmacoresistant childhood epilepsy, Lennox-Gastaut syndrome (LGS) [6]. Standard AEDs used to treat DS include valproate (VPA), clobazam (CLB), and stiripentol (STP; labeled to be used in combination with CLB and VPA) [7]. AEDs used to treat LGS include lamotrigine, felbamate, rufinamide, clonazepam, and nitrazepam. These AEDs are believed to treat seizures by altering GABA transmission [11, 12], and some may act on ion channels [11]. STP acts by inhibiting cytochrome P450 enzymes, indirectly increasing the concentration of other AEDs metabolized by those enzymes [13]
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More From: Int. Journal of Clinical Pharmacology and Therapeutics
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