拉莫三嗪用于癫痫治疗的有效浓度范围评价
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摘要
目的研究受试者工作特征(ROC)曲线及药物疗效-浓度曲线,确定拉莫三嗪的有效浓度范围,为癫痫患者的个体化用药提供参考。方法收集应用拉莫三嗪治疗,并进行血药浓度监测的癫痫患者病例,对资料进行回顾性分析。结果共有165例患者纳入研究,根据国际抗癫痫联盟治疗指南中的疗效评判标准,将患者分为有效组(121例,73. 33%)和无效组(44例,26. 67%)。有效组的稳态谷浓度为(4. 48±3. 01)μg·mL~(-1),无效组的稳态谷浓度为(3. 40±2. 76)μg·mL~(-1),差异有统计学意义(P <0. 05)。在ROC曲线评价中,以拉莫三嗪稳态谷浓度作为预测因子的诊断曲线下面积(AUC)=0. 632,显示出较高的预测准确性。当灵敏度为0. 760时,对应的ROC曲线上最佳临界值切点为2. 25μg·mL~(-1),说明当拉莫三嗪稳态谷浓度为2. 25μg·mL~(-1)时大多病例可获得满意疗效。在药物浓度-效应曲线中,拉莫三嗪稳态谷浓度在2. 48～7. 54μg·mL~(-1)时,发作得到明显控制,发作频次减少率较稳定,药物不良反应发生率较低。结论通过临床随访观察,初步探讨拉莫三嗪稳态谷浓度水平与其临床疗效的关系,确定拉莫三嗪稳态谷浓度的有效浓度范围为2. 25～7. 54μg·mL~(-1)。
Objective To establish a therapeutic range for lamotrigine plasma levels in the treatment of epilepsy by a receiver-operator characteristics( ROC) curve and a concentration effect curve,leading to a more personalized treatment. Methods A retrospective analysis of clinical data of patients with epilepsy was performed. The patients were treated with lamotrigine,and conduct therapeutic drug monitoring. Results A total of 165 patients were included in the study. According to the criteria for therapeutic efficacy in the International Leagul Against Epilesy( ILAE)treatment guidelines,patients were divided into effective group( n = 121,73. 33%) and ineffective group( n = 44,26. 67%),there was no statistically significant difference in sex,age and dosage between the two groups( P > 0. 05). The steady-state trough concentration of the effective group was( 4. 48 ± 3. 01) μg·mL~(-1)and that of ineffective group was( 3. 40 ± 2. 76) μg·mL~(-1),there was a statistically significant difference in the steady-state trough concentration of lamotrigine( P < 0. 05). In the ROC curve evaluation,the area under curve( AUC)of lamotrigine steady-state trough concentration as predictor for efficacy was 0. 632,which showed highly accurate predictions. When the sensitivity is 0. 760,the best threshold of response was 2. 25 μg · m L~(-1),which indicated that most patients would have good antiepileptic effects when steady-state trough concentration of lamotrigine was above 2. 25 μg·mL~(-1). In the drug concentration-effect curve,when the steady-state trough concentration of lamotrigine was between 2. 48 and 7. 54 μg ·mL~(-1),seizures were significantly controlled,the frequency of seizure frequency reduction was relatively stable,and the incidence of adverse reactions was low. Conclusion Through a clinical follow-up observations,we investigate the relationship between lamotrigine steady-state trough concentration and clinical efficacy. The effective concentration range of lamotrigine was determined as 2. 25-7. 54 μg·mL~(-1).
Objective To establish a therapeutic range for lamotrigine plasma levels in the treatment of epilepsy by a receiver-operator characteristics( ROC) curve and a concentration effect curve,leading to a more personalized treatment. Methods A retrospective analysis of clinical data of patients with epilepsy was performed. The patients were treated with lamotrigine,and conduct therapeutic drug monitoring. Results A total of 165 patients were included in the study. According to the criteria for therapeutic efficacy in the International Leagul Against Epilesy( ILAE)treatment guidelines,patients were divided into effective group( n = 121,73. 33%) and ineffective group( n = 44,26. 67%),there was no statistically significant difference in sex,age and dosage between the two groups( P > 0. 05). The steady-state trough concentration of the effective group was( 4. 48 ± 3. 01) μg·mL~(-1)and that of ineffective group was( 3. 40 ± 2. 76) μg·mL~(-1),there was a statistically significant difference in the steady-state trough concentration of lamotrigine( P < 0. 05). In the ROC curve evaluation,the area under curve( AUC)of lamotrigine steady-state trough concentration as predictor for efficacy was 0. 632,which showed highly accurate predictions. When the sensitivity is 0. 760,the best threshold of response was 2. 25 μg · m L~(-1),which indicated that most patients would have good antiepileptic effects when steady-state trough concentration of lamotrigine was above 2. 25 μg·mL~(-1). In the drug concentration-effect curve,when the steady-state trough concentration of lamotrigine was between 2. 48 and 7. 54 μg ·mL~(-1),seizures were significantly controlled,the frequency of seizure frequency reduction was relatively stable,and the incidence of adverse reactions was low. Conclusion Through a clinical follow-up observations,we investigate the relationship between lamotrigine steady-state trough concentration and clinical efficacy. The effective concentration range of lamotrigine was determined as 2. 25-7. 54 μg·mL~(-1).
引文
[1]VALENCIA I,PINOL-RIPOLL G,KHURANA D S,et al.Efficacy and safety of lamotrigine monotherapy in children and adolescents with epilepsy[J].Eur J Paediatr Neurol,2009,13(2):141-145.
[2]王成绪,宋志彬,廖卫平,等.拉莫三嗪治疗癫痫的剂量及血药浓度[J].中国药房,2003,14(9):546-548.
[3]廖卫平,宋志彬,杨少青,等.拉莫三嗪治疗癫癎的有效性与剂量、血药浓度及合并用药关系的研究[J].中国神经精神疾病杂志,2005,31(6):438-441.
[4]GLAUSER T,BEN-MENACHEM E,BOURGEOIS B,et al.IL-AE treatment guidelines:evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes[J].Epilepsia,2006,47(7):1094-1120.
[5]徐善森,张媞,周敬凯,等.高效液相色谱法测定人血浆中拉莫三嗪、奥卡西平及其代谢物浓度[J].中国临床药理学杂志,2015,31(12):1176-1179.
[6]FISHER R S,ACEVEDO C,ARZIMANOGLOU A,et al.ILAEofficial report:a practical clinical definition of epilepsy[J].Epilepsia,2014,55(4):475-482.
[7]RAMBECK B,WOLF P.Lamotrigine clinical pharmacokinetics[J].Clin Pharmacokinet,1993,25(6):433-443.
[8]MORRIS R G,BLACK A B,HARRIS A L,et al.Lamotrigine and therapeutic drug monitoring:retrospective survey following the introduction of a routine service[J].Br J Clin Pharmacol,1998,46(6):547-551.
[9]包军,何英,苏渊,等.影响拉莫三嗪稳态血药浓度的相关因素研究[J].中华儿科杂志,2001,39(8):457-460.
[10]PERRY P,ZEILMANN C,ARNDT S.Tricyclic antidepressant concentrations in plasma:an estimate of their sensitivity and specificity as a predictor of response[J].J Clin Psychopharmacol,1994,14(4):230-240.
[2]王成绪,宋志彬,廖卫平,等.拉莫三嗪治疗癫痫的剂量及血药浓度[J].中国药房,2003,14(9):546-548.
[3]廖卫平,宋志彬,杨少青,等.拉莫三嗪治疗癫癎的有效性与剂量、血药浓度及合并用药关系的研究[J].中国神经精神疾病杂志,2005,31(6):438-441.
[4]GLAUSER T,BEN-MENACHEM E,BOURGEOIS B,et al.IL-AE treatment guidelines:evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes[J].Epilepsia,2006,47(7):1094-1120.
[5]徐善森,张媞,周敬凯,等.高效液相色谱法测定人血浆中拉莫三嗪、奥卡西平及其代谢物浓度[J].中国临床药理学杂志,2015,31(12):1176-1179.
[6]FISHER R S,ACEVEDO C,ARZIMANOGLOU A,et al.ILAEofficial report:a practical clinical definition of epilepsy[J].Epilepsia,2014,55(4):475-482.
[7]RAMBECK B,WOLF P.Lamotrigine clinical pharmacokinetics[J].Clin Pharmacokinet,1993,25(6):433-443.
[8]MORRIS R G,BLACK A B,HARRIS A L,et al.Lamotrigine and therapeutic drug monitoring:retrospective survey following the introduction of a routine service[J].Br J Clin Pharmacol,1998,46(6):547-551.
[9]包军,何英,苏渊,等.影响拉莫三嗪稳态血药浓度的相关因素研究[J].中华儿科杂志,2001,39(8):457-460.
[10]PERRY P,ZEILMANN C,ARNDT S.Tricyclic antidepressant concentrations in plasma:an estimate of their sensitivity and specificity as a predictor of response[J].J Clin Psychopharmacol,1994,14(4):230-240.