Effects of CYP2C19 and CYP2C9 polymorphisms on the efficacy and plasma concentration of lacosamide in pediatric patients with epilepsy in China.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7603873 Publication Model: Electronic Cited Medium: Internet ISSN: 1432-1076 (Electronic) Linking ISSN: 03406199 NLM ISO Abbreviation: Eur J Pediatr Subsets: MEDLINE

Publication: Berlin : Springer Verlag
Original Publication: Berlin, New York, Springer-Verlag.

Cytochrome P-450 CYP2C19*/genetics ; Cytochrome P-450 CYP2C9*/genetics ; Epilepsy*/drug therapy ; Epilepsy*/genetics ; Epilepsy*/blood ; Anticonvulsants*/therapeutic use ; Anticonvulsants*/blood ; Anticonvulsants*/pharmacokinetics ; Anticonvulsants*/adverse effects ; Lacosamide*/pharmacokinetics ; Lacosamide*/therapeutic use ; Lacosamide*/blood ; Polymorphism, Genetic*; Humans ; Child ; Female ; Male ; Child, Preschool ; Prospective Studies ; China ; Adolescent ; Treatment Outcome ; Infant ; Genotype

To evaluate the effects of cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily C member 19 (CYP2C19) polymorphisms on the plasma concentrations, efficacy, and safety of lacosamide (LCM) among pediatric patients with epilepsy. This prospective study was conducted at two institutions. It included 215 pediatric patients with epilepsy who were under LCM. LCM plasma concentrations were quantified using validated ultra-performance liquid chromatography. CYP2C9 and CYP2C19 polymorphisms were analyzed in all pediatric patients in our hospital's Institute of Clinical Pharmacy research laboratory through polymerase chain reaction, agarose gel electrophoresis detection, gel recovery, and other steps. Seizure frequencies were recorded 3, 6, and 12 months after initiating LCM therapy and compared with the baseline monthly frequency. Clinical information, including efficacy, toxicity, and concomitant drugs, was collected. A total of 158 pediatric patients (73.5%) responded to LCM therapy. Of them, 77 patients reported adverse events while under LCM. The LCM plasma concentration was linearly correlated with its daily dose (r = 0.26, p < 0.001). Patients with adverse events reported higher LCM plasma concentrations (7.9 ± 4.0 µg/mL) than patients without adverse events (6.8 ± 3.0 µg/mL; p < 0.05). The poor metabolizer (PM) group demonstrated the highest concentration-to-dose ratio (1.7 ± 0.7 μg·mL ^-1 ·kg·mg ^-1 ) than the extensive metabolizer, intermediate metabolizer, and ultra-rapid metabolizer groups (0.8 ± 0.4, 1.0 ± 0.5, and 0.8 ± 0.4 μg·mL ^-1 ·kg·mg ^-1 , respectively). The PM group comprised the highest proportion of patients with effective LCM (9/11, 81.8%) and adverse events (7/11, 63.6%).
Conclusion: LCM plasma concentrations were strongly associated with its clinical efficacy and toxicity. CYP2C19 polymorphisms affect the plasma concentration and treatment efficacy in pediatric patients with epilepsy. CYP2C19 PMs with two no-function alleles are likely to have higher LCM plasma concentrations.
What Is Known: • LCM is metabolized by CYP2C19, CYP2C9, and CYP3A4 into pharmacologically inactive O-desmethyl-lacosamide; it primarily undergoes renal elimination. • Plasma LCM concentrations in patients treated with the recommended dose vary widely between and within individuals variability.
What Is New: • CYP2C19 polymorphisms affect the plasma concentration and treatment efficacy in Chinese pediatric patients with epilepsy. • CYP2C19 PMs with two no-function alleles are likely to have higher plasma LCM concentrations.
Competing Interests: Declarations. Ethics approval: This study was conducted in accordance with the Declaration of Helsinki’s principles. This study was authorized by the Medical Ethics Committee of People’s Hospital of Xinjiang Uygur Autonomous Region (No. KY2019120614), and informed consent was obtained from individual participants and their parents. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Moshe SL, Perucca E, Ryvlin P et al (2015) Epilepsy: new advances. Lancet 385:884–898. (PMID: 10.1016/S0140-6736(14)60456-625260236)
Pharma U Vimpat® (lacaosmide): EMA summary of product characteristics. https://www.emaeuropaeu/en/documents/product-information/vimpat-epar-product-information_enpdf.
US Food and Drug Administration (2013) Vimpat (lacosamide) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022253s024,022254s018,022255s010lbl.pdf ; [accessed1.2.17].
Vossler DG, Knake S, O’Brien TJ et al (2020) Efficacy and safety of adjunctive lacosamide in the treatment of primary generalised tonic-clonic seizures: a double- blind, randomised, placebo- controlled trial. J Neurol Neurosurg Psychiatry 91:1067–1075. (PMID: 10.1136/jnnp-2020-32352432817358)
Arabi M, Alsaadi T, Nasreddine W et al (2018) Efficacy and tolerability of treatment with lacosamide: Postmarketing experience from the Middle East region. Epilepsy Behav 84:118–121. (PMID: 10.1016/j.yebeh.2018.04.02029778846)
Biton V, Gil-Nagel A, Isojärvi J et al (2015) Safety and tolerability of lacosamide as adjunctive therapy for adults with partial-onset seizures: analysis of data pooled from three randomized, double-blind, placebo-controlled clinical trials. Epilepsy Behav 52:119–127. (PMID: 10.1016/j.yebeh.2015.09.00626414341)
Zadeh WW, Escartin A, Byrnes W et al (2015) Efficacy and safety of lacosamide as first add-on or later adjunctive treatment for uncontrolled partial-onset seizures: a multicentre open-label trial. Seizure 31:72–79. (PMID: 10.1016/j.seizure.2015.07.00126362380)
Zhao T, Li HJ, Ma L et al (2021) Safety, efficacy, and tolerability of lacosamide for the treatment of epilepsy in pediatric patients in Uygur, China. Epilepsy Behav 117:107814. (PMID: 10.1016/j.yebeh.2021.10781433611102)
Zhao T, Li HJ, Zhang HL et al (2023) Twelve-month efficacy of lacosamide monotherapy at maximal dose and tolerability for epilepsy treatment in pediatric patients: Real-world clinical experience. Pediatr Neurol 142:23–30. (PMID: 10.1016/j.pediatrneurol.2023.01.01836868054)
Zhao T, Yu LH, Zhang HL et al (2023) Long-term effectiveness and safety of lacosamide as adjunctive therapy in children and adolescents with refractory epilepsy: A real-world study. BMC Pediatr 23(1):249. (PMID: 10.1186/s12887-023-04039-53721055210199619)
Zhao T, Li HJ, Zhang HL et al (2023) Therapeutic drug monitoring of lacosamide in Chinese pediatric patients with epilepsy: efficacy and factors influencing the plasma concentration. Eur J Drug Metab Pharmacokinet 48(1):41–49. (PMID: 10.1007/s13318-022-00808-236418850)
Contin M, Albani F, Riva R et al (2013) Lacosamide therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs. Ther Drug Monit 35(6):849–852. (PMID: 10.1097/FTD.0b013e318290eacc23942540)
Yamamoto Y, Terada K, Araki Y et al (2020) Therapeutic monitoring of lacosamide in japanese patients with epilepsy: clinical response, tolerability, and optimal therapeutic range. Ther Drug Monit 42(5):754–759. (PMID: 10.1097/FTD.000000000000076432941398)
Cawello W, Stockis A, Andreas J et al (2014) Advances in epilepsy treatment: lacosamide pharmacokinetic profile. Ann N Y Acad Sci 1329:18–32. (PMID: 10.1111/nyas.1251325167889)
Cawello W, Boekens H, Bonn R (2012) Absorption, disposition, metabolic fate and elimination of the anti- epileptic drug lacosamide in humans: mass balance following intravenous and oral administration. Eur J Drug Metab Pharmacokinet 37:241–248. (PMID: 10.1007/s13318-012-0093-x22544644)
Svendsen T, Brodtkorb E, Baftiu A et al (2017) Therapeutic drug monitoring of lacosamide in Norway: focus on pharmacokinetic variability, efficacy and tolerability. Neurochem Res 42(7):2077–2083. (PMID: 10.1007/s11064-017-2234-828349359)
May TW, Helmer R, Bien CG et al (2018) Influence of dose and antiepileptic comedication on lacosamide serum concentrations in patients with epilepsy of different ages. Ther Drug Monit 40(5):620–627. (PMID: 10.1097/FTD.000000000000053830086089)
Scheffer IE, Berkovic S, Capovilla G et al (2017) ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:512–521. (PMID: 10.1111/epi.13709282760625386840)
Zhao T, Li HJ, Wang TT et al (2020) Development and validation of an innovative UPLC method to quantify lacosamide, oxcarbazepine and lamotrigine in the serum of children with epilepsy in China. Biomed Chromatogr 09:e5022.
Guidelines I (1989) Guidelines for clinical evaluation of antiepileptic drugs. Commission on Antiepileptic Drugs of the International League Against Epilepsy. Epilepsia 30:400–408. (PMID: 10.1111/j.1528-1157.1989.tb05317.x)
Shi YY, He L (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15:97–98. (PMID: 10.1038/sj.cr.729027215740637)
Svendsen T, Brodtkorb E, Baftiu A et al (2017) Therapeutic drug monitoring of lacosamide in Norway: focus on pharmacokinetic variability, efficacy and tolerability. Neurochem Res 42:2077–2083. (PMID: 10.1007/s11064-017-2234-828349359)
Cawello W (2015) Clinical pharmacokinetic and pharmacodynamic profile of lacosamide. Clin Pharmacokinet 54:901–914. (PMID: 10.1007/s40262-015-0276-025957198)
Markoula S, Teotonio R, Ratnaraj N et al (2014) Lacosamide serum concentrations in adult patients with epilepsy: the influence of gender, age, dose, and concomitant antiepileptic drugs. Ther Drug Monit 36:494–498. (PMID: 10.1097/FTD.000000000000005124562047)
Burns ML, Nikanorova M, Baftiu A et al (2019) Pharmacokinetic variability and clinical use of lacosamide in children and adolescents in Denmark and Norway. Ther Drug Monit 41(3):340–347. (PMID: 10.1097/FTD.0000000000000599)
Schaefer C, Cawello W, Waitzinger J et al (2015) Effect of age and sex on lacosamide pharmacokinetics in healthy adult subjects and adults with focal epilepsy. Clin Drug Investig 35(4):255–265. (PMID: 10.1007/s40261-015-0277-725708532)
Schultz L, Mahmoud SH (2020) Is therapeutic drug monitoring of lacosamide needed in patients with seizures and epilepsy? Eur J Drug Metab Pharmacokinet 45(3):315–349. (PMID: 10.1007/s13318-019-00601-831950342)
Winkler J, Schoemaker R, Stockis A (2019) Population pharmacokinetics of adjunctive lacosamide in pediatric patients with epilepsy. J Clin Pharmacol 59(4):541–547. (PMID: 10.1002/jcph.134030427550)
Hillenbrand B, Wisniewski I, Jürges U, Steinhoff BJ (2011) Add- on lacosamide: a retrospective study on the relationship between serum concentration, dosage, and adverse events. Epilepsy Behav 22:548–551. (PMID: 10.1016/j.yebeh.2011.08.03221962950)
Ahn SJ, Oh J, Kim DY et al (2022) Effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of lacosamide in Korean patients with epilepsy. Epilepsia 63(11):2958–2969. (PMID: 10.1111/epi.1739936039802)
Hyland R, Jones BC, Smith DA (2003) Identifica- tion of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos 31:540–547. (PMID: 10.1124/dmd.31.5.54012695341)
Theuretzbacher U, Ihle F, Derendorf H (2006) Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet 45:649–663. (PMID: 10.2165/00003088-200645070-0000216802848)
Chen L, Qin S, Xie J et al (2008) Genetic polymorphism analysis of CYP2C19 in Chinese Han populations from different geographic areas of mainland China. Pharmacogenomics 9(6):691–702. (PMID: 10.2217/14622416.9.6.69118518848)
Petrović J, Pešić V, Lauschke VM (2020) Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe. Eur J Hum Genet 28:88–94. (PMID: 10.1038/s41431-019-0480-831358955)
Doty P, Rudd GD, Stoehr T et al (2007) Lacosamide. Neurotherapeutics 4:145–148. (PMID: 10.1016/j.nurt.2006.10.002171990307479700)
Dean L (2012) Lacosamide therapy and CYP2C19 genotype. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kane MS, Kattman BL et al (eds) Medical genetics summaries. Bethesda, MD: National Center for Biotechnology Information (US).
Yukawa E, Mamiya K (2006) Effect of CYP2C19 genetic polymorphism on pharmacokinetics of phenytoin and phenobarbital in Japanese epileptic patients using non- linear mixed effects model approach. J Clin Pharm Ther 31:275–282. (PMID: 10.1111/j.1365-2710.2006.00712.x16789993)
Mamiya K, Hadama A, Yukawa E et al (2000) CYP2C19 polymorphism effect on phenobarbitone. Eur J Clin Pharmacol 55:821–825. (PMID: 10.1007/s00228005070310805060)
Inomata S, Nagashima A, Itagaki F et al (2005) CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia. Clin Pharm Therap 78:647–655. (PMID: 10.1016/j.clpt.2005.08.02016338280)

2022D01C154 Natural Science Foundation of Xinjiang Uygur Autonomous Region

Keywords: CYP2C19; CYP2C9; Efficacy; Lacosamide; Plasma concentration; Safety

EC 1.14.14.1 (Cytochrome P-450 CYP2C19)
EC 1.14.13.- (Cytochrome P-450 CYP2C9)
EC 1.14.14.1 (CYP2C19 protein, human)
0 (Anticonvulsants)
563KS2PQY5 (Lacosamide)
EC 1.14.13.- (CYP2C9 protein, human)

Date Created: 20241210 Date Completed: 20241210 Latest Revision: 20250102

20250102

10.1007/s00431-024-05897-6

39658609