Effect of Hepatic Impairment on the Pharmacokinetics of Fenfluramine and Norfenfluramine

Abstract Fenfluramine (Fintepla ® ) is approved for the treatment of seizures associated with the rare epileptic encephalopathies Dravet syndrome and Lennox–Gastaut syndrome. Fenfluramine is extensively metabolized; thus, patients with hepatic impairment (HI) might experience changes in exposure to fenfluramine or its metabolites. In this phase 1 study, we investigated the pharmacokinetics (PK) and safety of a single oral dose of 0.35 mg/kg fenfluramine in subjects with mild (n = 8), moderate (n = 8), or severe (n = 7) HI (Child–Pugh A/B/C, respectively) and healthy control subjects (n = 22) matched for sex, age, and BMI. All subjects underwent serial sampling to determine total plasma concentrations of fenfluramine and its active metabolite, norfenfluramine. Hepatic impairment was associated with increases in fenfluramine exposures, mainly area‐under‐the‐curve (AUC). Geometric least squares mean ratios (90% confidence intervals) for fenfluramine AUC 0‐∞ in mild, moderate, and severe HI versus healthy controls were 1.98 (1.36–2.90), 2.13 (1.43–3.17), and 2.77 (1.82–4.24), respectively. Changes in exposure to norfenfluramine in mild, moderate, and severe HI were minimal compared with normal hepatic function. Exposures to fenfluramine and norfenfluramine in all HI groups were within the ranges that have been characterized in the overall development program, including ranges examined in exposure–response relationships for efficacy and safety in patients, and determined to have an acceptable safety profile. Mild and moderate HI had a modest effect on fenfluramine exposure that was not clinically meaningful, whereas the higher fenfluramine exposure in severe HI may require dose reduction based on general caution in this population. The modest decrease in norfenfluramine exposure is not considered clinically relevant.