Lowering Fintepla Doses With Age or Diacomit Can Be Effective: Study
Reduced doses can control seizures without potential side effects
The blood levels of Fintepla (fenfluramine) are mostly within the lower range among treated children and adults with Dravet syndrome and other epileptic conditions, a study has found.
Still, these levels were enough to achieve good seizure control in most Dravet patients, further supporting the therapy’s potent effects, even at lower concentrations.
The data also suggested that Fintepla’s weight-based dose should be reduced with age and when combined with Diacomit (stiripentol), another Dravet-specific anti-seizure medication, to avoid excess concentrations and potential adverse events.
The study, “Therapeutic drug monitoring of fenfluramine in clinical practice: Pharmacokinetic variability and impact of concomitant antiseizure medications,” was published in the journal Epilepsia.
What is Fintepla?
Developed by Zogenix, Fintepla is an oral solution of low-dose fenfluramine that is approved as an add-on anti-seizure treatment for patients, 2 and older, with Dravet and Lennox-Gastaut syndrome, another rare childhood-onset epilepsy.
While fenfluramine was initially marketed to suppress appetite in obese adults, Fintepla, taken twice a day, was shown to effectively reduce seizure frequency in several clinical trials.
Due to its dose-dependent risk of heart-related adverse events, Fintepla’s daily dose is currently limited to 0.7 milligrams per kilogram of body weight (mg/kg; maximum of 26 mg/day) or 0.4 mg/kg (maximum of 17 mg/day) if combined with Diacomit, which is known to suppress fenfluramine breakdown.
“Up to now, no cardiovascular toxicity has been associated with the use of low-dose [fenfluramine] as an anticonvulsive drug, although the number of patients and treatment duration are still limited,” the researchers wrote.
Information about fenfluramine’s movement into, through, and out of the body (or pharmacokinetics) in pediatric patients “is sparse, and information about the therapeutic concentration in the treatment for epilepsy is lacking,” the researchers wrote.
Previous studies in obese adults suggested target therapeutic levels of 50−200 micrograms per liter (mcg/L).
With this in mind, a team of researchers at Antwerp University Hospital in Belgium set out to determine the blood levels and pharmacokinetics of fenfluramine and its main active byproduct norfenfluramine (norFFA) in people with treatment-resistant seizures. Of note, a couple of the researchers reported financial links to Zogenix, and the hospital may benefit from a royalty arrangement if Zogenix is successful in marketing Fintepla.
The researchers also analyzed potential links between these levels and the occurrence of adverse events, as well as the impact of simultaneous use of other anti-seizure medications, including Diacomit.
The team retrospectively analyzed 321 blood samples collected from 61 patients (33 males and 28 females) between June 2015 and December 2020. A total of 49 patients had Dravet, seven had Lennox-Gastaut syndrome, and seven were diagnosed with another infantile-onset epileptic condition.
Most patients (74%) received Fintepla within an investigator-initiated study (2011-004114-42), while 16 (26%) were treated in an ongoing international extension study (NCT02823145).
A median of four samples were collected from each patient. The median age of the patients was 13.8 years (range, 1.95–45.5 years). Most samples (68.2%) were taken from pediatric patients.
Fintepla was given for a median of 1.9 years (range of 1.2 months–32.2 years). It was used in 34 different anti-seizure treatment combinations, most frequently with valproate-containing medications like Depacon (sodium valproate), Topamax (topiramate), and a benzodiazepine.
What were the results of the Fintepla studies?
Results showed that with a median daily dose of 0.33 mg/kg, patients’ median blood fenfluramine levels were 41.4 mcg/L and those of norFFA were 28.1 mcg/L. These levels varied greatly within and between patients.
The variability “is probably related to [simultaneous medications], age, sampling–dose interval, and differences in metabolism,” the researchers wrote.
Fenfluramine and norFFA levels were significantly associated with the daily weight-adjusted dose, and significantly higher daily doses were used in pediatric patients. The fenfluramine concentration to weight-adjusted dose (C/D) ratio was significantly lower in children than in adults, who showed a 179% higher CD ratio.
This suggests that Fintepla may be broken down more quickly in children than in adults, highlighting the need to reduce the therapy’s dose with increasing age to avoid excess levels and potential adverse events.
Higher fenfluramine concentrations were significantly associated with fatigue and drowsiness, but not with anorexia.
Still, fenfluramine concentration was lower than 50 mcg/L in most samples (63.2%) and 15 patients (24.6%) never had levels higher than that. Three patients (4.9%) showed fenfluramine levels above 250 mcg/L, and all were treated also with Diacomit.
Consistent with previous reports, Diacomit was found to have a clear suppressive effect on fenfluramine metabolism. The nine patients treated with Fintepla plus Diacomit showed significantly higher fenfluramine levels (by 428%) and lower norFFA levels (by 83%) relative to those not on Diacomit.
All nine patients discontinued Diacomit during the study due to lack of efficacy. Adverse events were reported in all but one, suggesting that this combination treatment is also associated with a less favorable safety profile.
Sex and simultaneous use of other anti-seizure medications were not associated with significant variations in fenfluramine or norFFA C/D ratios.
The team also did not find a significant association between fenfluramine or norFFA levels and seizure reduction among Dravet patients not on Diacomit. However, “many patients (80%) achieved and maintained good seizure control with low [fenfluramine] levels [below 100 mcg/L],” including three patients with levels below 25 mcg/L, the researchers wrote.
This suggests that even low blood levels of fenfluramine are able to effectively reduce the frequency of seizures in Dravet patients.
“Despite the linear relation between [blood] concentration and dose, monitoring of [fenfluramine] (and its main metabolite norFFA) is clinically relevant due to the high interpatient pharmacokinetic variability,” the team wrote.
“Reduced weight-normalized doses are required with aging and in combination with [Diacomit] to avoid high [fenfluramine blood] concentrations and associated fatigue or somnolence [or drowsiness],” they concluded.
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