Therapeutic drug monitoring of fenfluramine in clinical practice: Pharmacokinetic variability and impact of concomitant antiseizure medications

Schoonjans, An‐Sofie; Roosens, Laurence; Dewals, Wendy; Paelinck, Bernard P.; Ceulemans, Berten

doi:10.1111/epi.17162

Cited by 15 publications

(9 citation statements)

References 33 publications

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“…It must also be emphasized that the need for TDM is much more prominent in patients with refractory epilepsy than in those with new‐onset seizures. Real‐life studies examining the clinical efficacy and tolerability of ASMs in relation to serum concentrations have in our experience been valuable in improving TDM services for the recently approved ASMs 47,48,69,87,88 . There is a need for studies in selected populations and for homogeneous indications for TDM to increase the level of evidence and benefits of use in terms of improved patient treatment and care, patient safety, and economical outcomes.…”

Section: Main Bodymentioning

confidence: 99%

“…10,11,67 Recent studies with young and vulnerable children include cannabidiol and fenfluramine. 68,69 Pregnancy is a time of particularly rapid and pronounced pharmacokinetic changes. Absorption may be affected by physiological changes or vomiting, volume of distribution can change due to an increase in body water and fat stores, and free, unbound concentrations of highly protein-bound drugs may increase.…”

Section: Definitionsmentioning

confidence: 99%

“…Children are in rapid development, and careful consideration should be given to physiology and organ function and maturation, pharmacokinetic features, and overall capacity for drug elimination 10,11,67 . Recent studies with young and vulnerable children include cannabidiol and fenfluramine 68,69 …”

Section: Main Bodymentioning

confidence: 99%

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Pharmacological aspects of antiseizure medications: From basic mechanisms to clinical considerations of drug interactions and use of therapeutic drug monitoring

Landmark

Eyal

Burns

et al. 2023

Epileptic Disorders

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Antiseizure medications (ASMs) are the cornerstone of treatment for patients with epilepsy. Several new ASMs have recently been introduced to the market, making it possible to better tailor the treatment of epilepsy, as well as other indications (psychiatry and pain disorders). For this group of drugs there are numerous pharmacological challenges, and updated knowledge on their pharmacodynamic and pharmacokinetic properties is, therefore, crucial for an optimal treatment outcome. This review focuses on educational approaches to the following learning outcomes as described by the International League Against Epilepsy (ILAE): To demonstrate knowledge of pharmacokinetics and pharmacodynamics, drug interactions with ASMs and with concomitant medications, and appropriate monitoring of ASM serum levels (therapeutic drug monitoring, TDM). Basic principles in pharmacology, pharmacokinetic variability, and clinically relevant approaches to manage drug interactions are discussed. Furthermore, recent improvements in analytical technology and sampling are described. Future directions point to the combined implementation of TDM with genetic panels for proper diagnosis, pharmacogenetic tests where relevant, and the use of biochemical markers that will all contribute to personalized treatment. These approaches are clinically relevant for an optimal treatment outcome with ASMs in various patient groups.

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Section: Main Bodymentioning

confidence: 99%

Section: Definitionsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological aspects of antiseizure medications: From basic mechanisms to clinical considerations of drug interactions and use of therapeutic drug monitoring

Landmark

Eyal

Burns

et al. 2023

Epileptic Disorders

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“…There is significant inter-and intra-patient variability in the plasma concentration of FFA and its metabolites. The plasma concentration was evaluated in 321 samples obtained from 61 patients (49 patients with Dravet syndrome and seven with LGS) [ 40 ]. Lower concentration was reported in younger patients when adjusted to weight, suggesting faster clearance in children.…”

Section: Fenfluramine Clinical Pharmacologymentioning

confidence: 99%

Fenfluramine: A Review of Pharmacology, Clinical Efficacy, and Safety in Epilepsy

Samanta

2022

Children

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Despite the availability of more than 30 antiseizure medications (ASMs), the proportion of patients who remain refractory to ASMs remains static. Refractory seizures are almost universal in patients with epileptic encephalopathies. Since many of these patients are not candidates for curative surgery, there is always a need for newer ASMs with better efficacy and safety profile. Recently, the anti-obesity medication fenfluramine (FFA) has been successfully repurposed, and various regulatory agencies approved it for seizures associated with Dravet and Lennox–Gastaut syndromes. However, there is a limited in-depth critical review of FFA to facilitate its optimal use in a clinical context. This narrative review discusses and summarizes the antiseizure mechanism of action of FFA, clinical pharmacology, and clinical studies related to epilepsy, focusing on efficacy and adverse effects.

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“…Fenfluramine, initially marketed as an anorexic agent, is currently approved in the United States and Europe for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome in patients 2 years of age and older 1,2 . Although fenfluramine is generally described even in recent articles as a single molecular entity, 3–8 the marketed product is a racemic mixture of d ‐ and l ‐enantiomers with different pharmacological properties 9,10 . In addition, d ‐ and l ‐fenfluramine are biotransformed in the body to the corresponding de‐ethylated active metabolites d ‐ and l ‐norfenfluramine, which also differ in their pharmacological profiles 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of d‐ and l‐norfenfluramine following their administration as individual enantiomers in rats

Erenburg,

Hamed,

Shaul

et al. 2023

Epilepsia

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The effect of fenfluramine and norfenfluramine enantiomers in rodent seizure models and their correlation with the pharmacokinetics of d‐ and l‐fenfluramine in rats have been reported recently. To complement these findings, we investigated the pharmacokinetics of d‐ and l‐ norfenfluramine in rat plasma and brain. Sprague‐Dawley rats were injected intraperitoneally with 20 mg/kg and 1 mg/kg l‐ norfenfluramine. A 1 mg/kg dose of d‐norfenfluramine was used because higher doses caused severe toxicity. The concentration of each enantiomer in plasma and brain was determined at different time points by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were compared between norfenfluramine enantiomers, and with those reported previously for fenfluramine enantiomers after a 20 mg/kg, i.p., dose. All enantiomers were absorbed rapidly and eliminated, with half‐lives ranging from 0.9 h (l‐fenfluramine) to 6.1 h (l‐ norfenfluramine, 20 mg/kg) in plasma, and from 3.6 h (d‐fenfluramine) to 8.0 h (l‐fenfluramine) in brain. Brain‐to‐plasma concentration ratios ranged from 15.4 (d‐fenfluramine) to 27.6 (d‐norfenfluramine), indicating extensive brain penetration. The fraction of d‐ and l‐fenfluramine metabolized to norfenfluramine was estimated to be close to unity. This work is part of ongoing investigations to determine the potential value of developing enantiomerically pure l‐fenfluramine or l‐norfenfluramine as follow‐up compounds to the marketed racemic fenfluramine.

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Therapeutic drug monitoring of fenfluramine in clinical practice: Pharmacokinetic variability and impact of concomitant antiseizure medications

Cited by 15 publications

References 33 publications

Pharmacological aspects of antiseizure medications: From basic mechanisms to clinical considerations of drug interactions and use of therapeutic drug monitoring

Pharmacological aspects of antiseizure medications: From basic mechanisms to clinical considerations of drug interactions and use of therapeutic drug monitoring

Fenfluramine: A Review of Pharmacology, Clinical Efficacy, and Safety in Epilepsy

Pharmacokinetics of d‐ and l‐norfenfluramine following their administration as individual enantiomers in rats

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