Evaluation of the Effect of Eslicarbazepine Acetate on the Pharmacokinetics of Perampanel in Rats by Isotope-Dilution-UHPLC-MS/MS

Purpose The present study aimed to establish and validate an isotope-dilution-UHPLC-MS/MS method for the determination of perampanel (PER) concentration and investigate the effect of eslicarbazepine acetate (ESL) on the pharmacokinetics of PER in rats. Methods The rats were randomly divided into the control (0.5% CMC-Na) and experimental groups (ESL, 72 mg/kg), with six rats in each group. A single dose of PER (1 mg/kg) was administered after a week of repetitive 0.5% CMC-Na or ESL dosing (72 mg/kg); then, plasma samples were collected. Perampanel-d5 (PER-d5) was used as the internal standard (IS), liquid-liquid extraction of plasma samples was carried out using ethyl acetate, and chromatographic separation was carried out on a Titank C18 column (2.1 mm × 50 mm, 3.0 μm) using a gradient mobile phase consisting of 0.1% formic acid and acetonitrile at a flow rate of 0.3 mL/min. Results PER had good linearity (0.3–600 ng/mL, r >0.999), and the accuracy, precision, recovery rate, and matrix effects (ME) met the Food and Drug Administration (FDA) guidelines. Compared to the control group, the area under the curve AUC0→t, AUC0→∞, and Cmax of PER in the experimental group decreased by 30.28%, 30.34%, and 46.94%, respectively, and CL increased by 32.08%. Conclusion ESL could induce the metabolism of PER in rats and decreases plasma exposure to PER. Thus, the concomitant treatment with ESL may require a high dose of PER to achieve the same efficacy.

[1]  H. Lerche.  Drug-resistant epilepsy — time to target mechanisms , 2020, Nature Reviews Neurology.

[2]  L. Tomycz,et al.  Deciphering the surgical treatment gap for drug‐resistant epilepsy (DRE): A literature review , 2020, Epilepsia.

[3]  W. Löscher,et al.  Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options , 2020, Pharmacological Reviews.

[4]  K. Chu,et al.  Usefulness of saliva for perampanel therapeutic drug monitoring , 2020, Epilepsia.

[5]  P. Kwan,et al.  What has been the impact of new drug treatments on epilepsy? , 2020, Current opinion in neurology.

[6]  G. Zaccara,et al.  Pharmacodynamic interactions of antiepileptic drugs: From bench to clinical practice , 2020, Epilepsy & Behavior.

[7]  G. Gigli,et al.  Pharmacokinetic and pharmacodynamic considerations for the clinical efficacy of perampanel in focal onset seizures , 2018, Expert opinion on drug metabolism & toxicology.

[8]  L. Nowak,et al.  Modulation of AMPA Receptor Gating by the Anticonvulsant Drug, Perampanel. , 2018, ACS medicinal chemistry letters.

[9]  J. Peltola,et al.  Dibenzazepine Agents in Epilepsy: How Does Eslicarbazepine Acetate Differ? , 2018, Neurology and Therapy.

[10]  Francesco Perini,et al.  A Liquid Chromatography-Mass Spectrometry Assay for Determination of Perampanel and Concomitant Antiepileptic Drugs in the Plasma of Patients With Epilepsy Compared With a Fluorescent HPLC Assay , 2018, Therapeutic drug monitoring.

[11]  B. Bourgeois,et al.  Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy , 2018, Epilepsy currents.

[12]  B. Bourgeois,et al.  Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy , 2018, Neurology.

[13]  A. Sahu,et al.  Pharmacokinetics and brain uptake study of novel AMPA receptor antagonist perampanel in SD rats using a validated UHPLC‐QTOF‐MS method , 2018, Journal of pharmaceutical and biomedical analysis.

[14]  B. Abou-Khalil.  Selecting Rational Drug Combinations in Epilepsy , 2017, CNS Drugs.

[15]  S. Benbadis,et al.  Carbamazepine-related antiepileptic drugs for the treatment of epilepsy - a comparative review , 2016, Expert opinion on pharmacotherapy.

[16]  J. Ferry,et al.  Perampanel efficacy and tolerability with enzyme-inducing AEDs in patients with epilepsy , 2015, Neurology.

[17]  K. Kusano,et al.  High-performance liquid chromatography-tandem mass spectrometry method for the determination of perampanel, a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist in human plasma. , 2015, Journal of pharmaceutical and biomedical analysis.

[18]  P. Soares-da-Silva,et al.  Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: A comparison with carbamazepine, oxcarbazepine and lacosamide , 2015, Neuropharmacology.

[19]  P. Patsalos.  The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist , 2015, Epilepsia.

[20]  W. W. Q. Hsu,et al.  Systematic Review and Meta-Analysis of the Efficacy and Safety of Perampanel in the Treatment of Partial-Onset Epilepsy , 2013, CNS Drugs.

[21]  P. Patsalos.  Drug Interactions with the Newer Antiepileptic Drugs (AEDs)—Part 2: Pharmacokinetic and Pharmacodynamic Interactions Between AEDs and Drugs Used to Treat Non-Epilepsy Disorders , 2013, Clinical Pharmacokinetics.

[22]  P. Patsalos.  Drug Interactions with the Newer Antiepileptic Drugs (AEDs)—Part 1: Pharmacokinetic and Pharmacodynamic Interactions Between AEDs , 2013, Clinical Pharmacokinetics.

[23]  M. Bialer,et al.  Pharmacokinetics and drug interactions of eslicarbazepine acetate , 2012, Epilepsia.

[24]  P. Kwan,et al.  In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P‐glycoprotein , 2011, Epilepsia.

[25]  S. Johannessen,et al.  Antiepileptic Drug Interactions - Principles and Clinical Implications , 2010, Current neuropharmacology.

[26]  G. Mathern,et al.  Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies , 2009, Epilepsia.

[27]  M Lindsay,et al.  Epilepsy in adults. , 1983, Nursing.

[28]  Zhaohui J. Cai,et al.  Pretreatment data is highly predictive of liver chemistry signals in clinical trials , 2012, Drug design, development and therapy.