Severe Perampanel Toxicity in a Pediatric Patient With Prolonged Symptoms

Winkler, Garret A.; Minns, Alicia B.; Kreshak, Allyson A.

doi:10.1016/j.jemermed.2021.07.011

Cited by 4 publications

(3 citation statements)

References 10 publications

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“…In the EU and USA, PRP is widely used as an adjunctive agent for epilepsy patients over 12 year old suffering partial-onset seizures (POS) and primary generalized tonic–clonic seizures (GTCS) with or without secondary generalized seizures. However, with the widespread use of PRP, there are some clinical reports of hepatotoxicity cases accompanied with an increase in γ-glutamyl transpeptidase (GTP) and AST/ALT. , The mechanisms involved in the reported liver injury remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Activation of Perampanel Mediated by CYP1A2

Ding

Wang

Zhang

et al. 2022

Chem. Res. Toxicol.

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Perampanel (PRP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonist with high selectivity, has been used as a new adjuvant for the treatment of fractional seizures with or without primary generalized tonic–clonic seizures and secondary generalized seizures in epilepsy patients over the age of 12. Adverse events such as liver injury have been reported during the clinical application of PRP. The purpose of the study is to explore the in vitro and in vivo metabolic activation of PRP. Two GSH conjugates were detected in rat liver microsomal incubations containing PRP, GSH, and NADPH. The two GSH conjugates were both obtained from the bile of rats and rat primary hepatocytes after exposure to PRP. Similar microsomal incubations complemented with N-acetylcysteine (NAC) in place of GSH offered two NAC conjugates. As expected, the NAC conjugates were detected in the urine of PRP-treated rats. One of the two NAC conjugates was identified as NAC conjugate 12 verified by chemical synthesis. The individual human recombinant P450 enzyme incubation assay demonstrated that CYP1A2 dominated the catalysis for the metabolic activation of PRP. Pretreatment with α-naphthoflavone (NTF) decreased the formation of PRP-derived GSH conjugates in both livers of rats and cultured primary hepatocytes after being treated with PRP. Additionally, NTF was found to decrease the susceptibility of primary hepatocytes to the cytotoxicity of PRP. The findings indicate that PRP was metabolized to the corresponding epoxide, which could participate in PRP-induced cytotoxicity.

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Section: Introductionmentioning

confidence: 99%

“…However, with the widespread use of PRP, there are some clinical reports of hepatotoxicity cases accompanied with an increase in γ-glutamyl transpeptidase (GTP) and AST/ALT. 4,5 The mechanisms involved in the reported liver injury remain unknown.…”

Section: ■ Introductionmentioning

confidence: 99%

Metabolic Activation of Perampanel Mediated by CYP1A2

Ding

Wang

Zhang

et al. 2022

Chem. Res. Toxicol.

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“…[ 13 , 14 ] Currently, most studies on pediatric patients have focused on patients who were >12 years of age. However, dose-related toxicity has been reported in patients aged ≤2 years who received perampanel [ 15 , 16 ] ; hence, it is important to assess the safety and tolerability of treatment protocols in younger pediatric patients with epilepsy. This study reported the effectiveness and tolerability of perampanel in pediatric patients ≤12 years of age with refractory epilepsy.…”

Section: Introductionmentioning

confidence: 99%

Effectiveness and tolerability of adjunctive perampanel in pediatric patients (aged 4–12 years) with refractory epilepsy: An observational study

Chu

Tang

2022

Medicine

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Information on the effects of perampanel in Chinese children ≤12 years of age with refractory epilepsy is limited; thus, we conducted an observational study to assess the effectiveness, safety, and tolerability of adjunctive perampanel in this pediatric population. In this study, we reviewed the medical records of pediatric patients aged 4 to 12 years with refractory epilepsy who were admitted to Children’s Hospital of Soochow University and prescribed perampanel between January 2020 and January 2021. Effectiveness of perampanel was measured by 50% responder rates, seizure-freedom rates, and retention rates for up to 48 weeks. Adverse events were monitored and recorded throughout the study. A total of 34 patients (male, n = 15) who exhibited refractory epilepsy were included in this study, and 64.71% of patients had focal-onset seizures combined with generalized epilepsy. The mean (± standard deviation) age of patients was 7.21 (± 2.12) years, with a mean (± standard deviation) age at seizure onset of 4.57 (± 2.59) years. After the addition of perampanel, the 50% responder rates at 4, 8, 12, 24, 36, and 48 weeks were 37.50% (12/32), 43.75% (14/32), 53.13% (17/32), 59.38% (19/32), 59.38% (19/32), and 62.07% (18/29). Two patients withdrew from perampanel treatment due to adverse events in the first 2 weeks. Adverse events were reported by 44.12% (15/34) of patients, and the retention rates at 36 and 48 weeks were 94.12% (32/34) and 85.29% (29/34), respectively. Overall, perampanel exhibited good effectiveness, safety, and tolerability in the treatment of pediatric patients (aged 4–12 years) with refractory epilepsy. These findings suggest that personalized treatment and better baseline seizure control may increase the responder rate and retention rate of perampanel.

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Anti-epileptic medications

Maroney

Marković²

2022

Side Effects of Drugs Annual

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Severe Perampanel Toxicity in a Pediatric Patient With Prolonged Symptoms

Cited by 4 publications

References 10 publications

Metabolic Activation of Perampanel Mediated by CYP1A2

Metabolic Activation of Perampanel Mediated by CYP1A2

Effectiveness and tolerability of adjunctive perampanel in pediatric patients (aged 4–12 years) with refractory epilepsy: An observational study

Anti-epileptic medications

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