Yoshiaki Yamamoto1, Yuka Shiratani2, Shoko Asai2, Naotaka Usui2, Takuji Nishida2, Katsumi Imai2, Yoshiyuki Kagawa3, Yukitoshi Takahashi4. 1. Department of Clinical Research, NHO, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Shizuoka, 420-8688, Japan; Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan. Electronic address: yamamoto.yoshiaki.sx@mail.hosp.go.jp. 2. Department of Clinical Research, NHO, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Shizuoka, 420-8688, Japan. 3. Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan; Laboratory of Clinical Pharmacokinetics and Drug Safety, Shizuoka General Hospital, 4-27-1 Kita Ando, Shizuoka, 420-8527, Japan. 4. Department of Clinical Research, NHO, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Shizuoka, 420-8688, Japan; Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan.
Abstract
OBJECTIVE: We aimed to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum perampanel concentration and to correlate the concentration with clinical response and tolerability. METHODS: A total of 4224 serum samples were obtained from 763 pediatric, adolescent, and adult patients for routine therapeutic drug monitoring. We compared the extent of enzyme induction between cytochrome P450 3A4 (CYP3A4) inducer regimens and built a statistical model to estimate the serum perampanel concentration that considered use of CYP3A4 inducers and inhibitors. To assess the tolerability and clinical effectiveness of perampanel therapy, we used the nested case-control approach. The case group was matched with the control group for age, sex, epilepsy type, and perampanel exposure periods. RESULTS: Concomitant use of the inducers phenytoin, carbamazepine, and phenobarbital dose-dependently reduced the perampanel concentration by 51 %, 67 %, and 37 %, respectively. The estimate model showed a good correlation between the predicted and measured concentrations (r2 = 0.62, p < 0.001). In 206 patients, the seizure reduction from baseline was > 50 % and the median perampanel concentration was 351 ng/mL (interquartile range, 191-603 ng/mL). Adverse events, such as somnolence, dizziness, and irritability, were experienced by 185 patients. The responder odds ratio was 5.1-fold higher in patients with a serum concentration > 600 ng/mL than in those with a serum concentration < 200 ng/mL; however, the former group had a 7.9-fold higher incidence of adverse events. CONCLUSION: Therapeutic drug monitoring is clinically useful to assess drug interactions between perampanel and CYP3A4 inducers and inhibitors. We recommend that the target concentration of perampanel is initially set at 200-600 ng/mL. Serum concentrations > 600 ng/mL were associated with greater anti-seizure effects but had an increased risk of adverse events.
OBJECTIVE: We aimed to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum perampanel concentration and to correlate the concentration with clinical response and tolerability. METHODS: A total of 4224 serum samples were obtained from 763 pediatric, adolescent, and adult patients for routine therapeutic drug monitoring. We compared the extent of enzyme induction between cytochrome P450 3A4 (CYP3A4) inducer regimens and built a statistical model to estimate the serum perampanel concentration that considered use of CYP3A4 inducers and inhibitors. To assess the tolerability and clinical effectiveness of perampanel therapy, we used the nested case-control approach. The case group was matched with the control group for age, sex, epilepsy type, and perampanel exposure periods. RESULTS: Concomitant use of the inducers phenytoin, carbamazepine, and phenobarbital dose-dependently reduced the perampanel concentration by 51 %, 67 %, and 37 %, respectively. The estimate model showed a good correlation between the predicted and measured concentrations (r2 = 0.62, p < 0.001). In 206 patients, the seizure reduction from baseline was > 50 % and the median perampanel concentration was 351 ng/mL (interquartile range, 191-603 ng/mL). Adverse events, such as somnolence, dizziness, and irritability, were experienced by 185 patients. The responder odds ratio was 5.1-fold higher in patients with a serum concentration > 600 ng/mL than in those with a serum concentration < 200 ng/mL; however, the former group had a 7.9-fold higher incidence of adverse events. CONCLUSION: Therapeutic drug monitoring is clinically useful to assess drug interactions between perampanel and CYP3A4 inducers and inhibitors. We recommend that the target concentration of perampanel is initially set at 200-600 ng/mL. Serum concentrations > 600 ng/mL were associated with greater anti-seizure effects but had an increased risk of adverse events.
Authors: Julia Izsak; Henrik Seth; Margarita Iljin; Stephan Theiss; Hans Ågren; Keiko Funa; Ludwig Aigner; Eric Hanse; Sebastian Illes Journal: Transl Psychiatry Date: 2021-05-12 Impact factor: 6.222