Rationale:
Fenfluramine (FFA) reduces seizure incidence in the rare epileptic encephalopathies Dravet syndrome (DS) and Lennox-Gastaut syndrome. Treatment of these seizures often requires multiple anti-seizure medications (ASMs), some of which may alter systemic exposure to FFA. In DS, common ASM additions to FFA include stiripentol (STP), clobazam (CLB), and valproate (VPA). Additionally, it is of interest whether intrinsic factors such as age, sex, race, creatinine clearance (CLcr), and comorbidities can influence exposure to FFA and its active metabolite norfenfluramine (nFFA). Understanding the impact of these factors, in addition to drug-drug interactions, would help in selecting a dose that will provide good tolerability during therapy with FFA. Our objective was to use population pharmacokinetic (PPK) analyses to describe the steady-state systemic exposure to FFA and nFFA in DS patients and quantify the potential impact of population characteristics and concomitant medications.
Methods:
Data from two Phase One studies (144 healthy participants) and two Phase Three studies in DS (158 patients, sparsely sampled) were pooled to develop a robust PPK model. The model was used to estimate post hoc steady-state exposure (C
min, C
max, AUC
0-24) to FFA and nFFA, variability, dose proportionality, and to determine if covariates and variables such as concomitant ASMs affected FFA and nFFA pharmacokinetics (PK).
Results:
The PPK model consisted of two compartments for FFA, first-order absorption of FFA, allowance for pre-systemic formation of nFFA, two compartments for nFFA, and linear clearance for both compounds. The only covariates of significance were body weight (invoking weight-based allometric scaling of clearance and volume of distribution terms) and concomitant STP. In patients who received FFA (free base) 0.7 mg/kg/d alone (maximum 26 mg/d, twice-daily), geometric mean steady-state FFA C
min was 46.9 ng/mL, C
max was 68.0 ng/mL and AUC
0-24 was 1390 ng·h/mL; nFFA C
min was 34.1 ng/mL, C
max was 37.8 ng/mL and AUC
0-24 was 872 ng·h/mL. Variability (%CV) in PK parameters ranged from 41% to 56%. Exposures of FFA and nFFA increased nearly dose proportionally in DS patients who received 0.2 mg/kg/d or 0.7 mg/kg/d FFA (Table). Model-based evaluations suggest a 166% increase in FFA AUC
0-24, and a 38% decrease in nFFA AUC
0-24, in patients receiving 0.2 mg/kg/d FFA (maximum 17 mg/d) with concomitant STP compared to 0.2 mg/kg/d FFA (maximum 26 mg/d) without STP, indicating a decrease in apparent clearance of FFA with STP. Inclusion of CLB and VPA had no impact on PPK model-derived exposure to FFA or nFFA. No other subject-specific factors explained a significant portion of the interindividual variability in FFA/nFFA PK.
Conclusions:
A comprehensive modeling approach allowed for the evaluation of factors that could potentially impact the PK of FFA and/or nFFA in patients with DS. These data will help clinicians select an appropriate dose of FFA that can be added to current regimens for treatment of DS and other pediatric-onset epilepsies.
Funding:
Zogenix, Inc.