Abstract：OBJECTIVE To estimate and optimize the dosage regimens of lamotrigine for epileptic children with the utilization of Monte Carlo simulation based on the pharmacokinetic/pharmacodynamic principle of antiepileptic drugs. METHODS Population pharmacokinetic data of lamotrigine for epileptic children in China was obtained from the published literatures. Ten thousand times Monte Carlo simulation were performed for 25 dosing regimens for epileptic children aged 2 to 12 years and 33 dosing regimens for post-12-year-old epileptic children to obtain the steady-state concentration (css) and the probability of target attainment (PTA). Based on this, the rationality of the dosing regimens were evaluated and the optimal dosing regimen was screened. RESULTS Within the recommended dosage range of lamotrigine for epileptic children aged 2 to 12 years, six of the nine pre-established maintenance-phase regimens were found that the PTA that lamotrigine plateau concentrations distributed in therapeutic window ranged from 80.54% to 90.69%, meanwhile the PTA that plateau concentrations distributed over the therapeutic window ranged from 0.41% to 12.50%, and the predicted mean of css ranged from 4.62 to 9.28 mg·L-1, so each was the optimization regimen. Among the 15 dosage regimens of lamotrigine for epileptic children over 12 years old, eleven of fifteen pre-established maintenance-phase regimens were found that the PTA that lamotrigine plateau concentrations distributed in therapeutic window ranged from 91.51% to 100.00%, the PTA that plateau concentrations distributed over the therapeutic window ranged from 0.00% to 8.49%, and the predicted mean of css ranged from 6.21 to 12.44 mg·L-1, so each was the optimization regimen. Interestingly, five off-label regimens of lamotrigine (12.5, 25, 37.5 mg, bid and 25, 50 mg, qd) in combination with valproic acid were found that the PTA that lamotrigine plateau concentrations distributed in therapeutic window was 100.00%, and the predicted mean of css ranged from 3.84 to 11.51 mg·L-1, which were superior to the recommended dosage (100-200 mg·d-1), indicating use with caution could be acceptable. CONCLUSION In most cases, lamotrigine can be given according to drug instructions to obtain satisfactory therapeutic effect. However, some of off-label drug of use have certain rationality and necessity.
王鸣璐, 陶玉瑛, 李惟滔, 肇丽梅. 基于蒙特卡罗模拟法评价和优化拉莫三嗪儿童给药方案[J]. 中国药学杂志, 2019, 54(20): 1706-1714.
WANG Ming-lu, TAO Yu-ying, LI Wei-tao, ZHAO Li-mei. Evaluation and Optimization of the Dosage Regimens of Lamotrigine for Epileptic Children Based on Monte Carlo Simulation. Chinese Pharmaceutical Journal, 2019, 54(20): 1706-1714.
WHELESS J W, CLARKE D F, ARZIMANOGLOU A, et al. Treatment of pediatric epilepsy: European expert opinion, 2007[J]. Epileptic Disord, 2007, 9(4):353-412.
[2]
NOSKOVA T Y, ABAIMOV D A, SARIEV A K, et al. The clinical significance of the lamotrigine pharmacokinetic variability[J]. Zh Nevrol Psikhiatr Im S S Korsakova, 2018, 118(1):23-29.
[3]
JOHANNESSEN S I, TOMSON T. Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed?[J]. Clin Pharmacokinet, 2006, 45(11):1061-1075.
[4]
JOHANNESSEN L C, BAFTIU A, TYSSE I, et al. Pharmacokinetic variability of four newer antiepileptic drugs, lamotrigine, levetiracetam, oxcarbazepine, and topiramate: a comparison of the impact of age and comedication[J]. Ther Drug Monit, 2012, 34(4):440-445.
[5]
FDA. LAMICTAL label [EB/OL]. GlaxoSmithKline, USA, 2015 (2015-03-24) [2019-10-18]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf.
[6]
SFDA. Label information of lamotrigine [EB/OL]. GlaxoSmithKline (Tianjin) Co., Ltd, China, 2014 (2014-06-28) [2019-10-18]. https://health.gsk-china.com/content/dam/global/hcpportal/zh_CN/PI/lamictal.pdf.
[7]
SHANG D W, WEN Y G, WANG Z Z. Clinical pharmacist guidelines for individualized administration of lamotrigine[J]. Pharm Today (今日药学), 2016, 26(4):217-224.
[8]
China Association Against Epilepsy. Clinical Guidelines for Diagnosis and Treatment: Epilepsy Catalogue (Amended 2015)[临床诊疗指南:癫痫病分册(2015修订版)][M]. Beijing: People′s Medical Publishing House, 2015.
[9]
CAI H F, ZHENG B, LIU M B. A survey of off-label use of antiepileptic drugs in children[J]. Chin J Hosp Pharm (中国医院药学杂志), 2015, 35(6):551-554.
[10]
ZHANG B, ZHU Z. Application of Monte Carlo simulation in antibiotic pharmacokinetics and pharmacodynamics[J]. Chin Pharm J(中国药学杂志), 2008, 43(4):241-244.
[11]
National Prescription Editorial Committee. National Formulary (Volume of Chemical and Biological Products·Children’s Edition) [中国国家处方集(化学药品与生物制品卷·儿童版)] [M]. Beijing: Military Science Publishing House, 2013: 80-81.
[12]
Clinical Child Pharmacology Society, Pediatric Academy of Chinese Medical Association, Editorial Committee of Chinese Journal of Pediatrics. The expert consensus of chinese pediatric off-label drug of use[J]. Chin J Pediatr (中华儿科杂志), 2016, 54(2):101-103.
[13]
PATSALOS P N, BERRY D J, BOURGEOIS B F, et al. Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies[J]. Epilepsia, 2008, 49(7):1239-1276.
[14]
HIEMKE C, BERGEMANN N, CLEMENT H W, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology:update 2017[J]. Pharmacopsychiatry, 2018, 51(1-2):9-62.
[15]
HE D K, WANG L, QIN J, et al. Research on population pharmacokinetics of Lamotrigine in children with epilepsy[J]. J Shanghai Jiaotong Univ(Med Sci) (上海交通大学学报:医学版), 2010, 30(2):135-139.
[16]
ZHANG S, WANG L, LU W. Population pharmacokinetics of lamotrigine in Chinese children with epilepsy[J]. Chin J Contemp Pediatri(中国当代儿科杂志), 2008, 10(2):105-109.
[17]
MILOSHESKA D, LORBER B, VOVK T, et al. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: influence of polymorphism of UDP-glucuronosyltransferases and drug transporters[J]. Br J Clin Pharmacol, 2016, 82(2):399-411.
[18]
YASAM V R, JAKKI S L, SENTHIL V, et al. A pharmacological overview of lamotrigine for the treatment of epilepsy[J]. Expert Rev Clin Pharmacol, 2016, 9(12):1533-1546.
[19]
KORISTKOVA B, GRUNDMANN M, BROZMANOVA H, et al. Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients[J]. Basic Clin Pharmacol Toxicol, 2019, 125(1):26-33.
[20]
WEINTRAUB D, BUCHSBAUM R, RESOR S R, et al. Effect of antiepileptic drug comedication on lamotrigine clearance[J]. Arch Neurol, 2005, 62(9):1432-1436.
[21]
ZHANG Z B, JI S M, HAN Y, et al. Population pharmacokinetic models of lamotrigine in different age groups of Chinese children with epilepsy[J]. Eur J Clin Pharmacol, 2017, 73(4):445-453.
2019, Vol. 54 
