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

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.

A pilot, open‐label study of the effectiveness and tolerability of low‐dose ZX008 (fenfluramine HCl) in Lennox‐Gastaut syndrome

“…In vitro drug‐drug interaction studies have suggested that both fenfluramine and its active metabolite norfenfluramine may be weak CYP2D6 inhibitors and weak inducers of CYP2B6 and CYP3A4 (Brooks Boyd, written communication, July 2018). In human clinical studies, combination regimens of the antiepileptic drugs stiripentol, clobazam, and valproate increased the exposure of fenfluramine with the expected reduction in its metabolite norfenfluramine, presumably by inhibiting CYP2C19 and CYP3A4, and CYP1A2, CYP2C9, and CYP2D6 . The results of these studies suggest that dose adjustments may be needed to maintain therapeutic plasma concentrations of ZX008 in some combination regimens.…”

“…Fenfluramine is metabolized primarily by CYP1A2, CYP2B6, and CYP2D6, with additional metabolism by CYP2C9, CYP2C19, and CYP3A4 . Because of the large number of metabolism pathways, it is unlikely that the drugs affecting a single pathway will have a significant potential to affect fenfluramine pharmacokinetics.…”

“…Fenfluramine is metabolized primarily by CYP1A2, CYP2B6, and CYP2D6, with additional metabolism by CYP2C9, CYP2C19, and CYP3A4. 25 Because of the large number of metabolism pathways, it is unlikely that the drugs affecting a single pathway will have a significant potential to affect fenfluramine pharmacokinetics. In vitro drug-drug interaction studies have suggested that both fenfluramine and its active metabolite norfenfluramine may be weak CYP2D6 inhibitors and weak inducers of CYP2B6 and CYP3A4 (Brooks Boyd, written communication, July 2018).…”

“…In human clinical studies, combination regimens of the antiepileptic drugs stiripentol, clobazam, and valproate increased the exposure of fenfluramine with the expected reduction in its metabolite norfenfluramine, presumably by inhibiting CYP2C19 and CYP3A4, and CYP1A2, CYP2C9, and CYP2D6. [25][26][27][28] The results of these studies suggest that dose adjustments may be needed to maintain therapeutic plasma concentrations of ZX008 in some combination regimens. However, ZX008 did not significantly affect the pharmacokinetics of a triple antiepileptic drug combination regimen consisting of clobazam, valproate, and stiripentol.…”

“…However, ZX008 did not significantly affect the pharmacokinetics of a triple antiepileptic drug combination regimen consisting of clobazam, valproate, and stiripentol. 25 Additional studies are needed to determine the potential interactions of ZX008 in combination with other antiepileptic drugs that may be used in LGS regimens (ie, lamotrigine, rufinamide, and topiramate).…”