The effect of poor compliance on the pharmacokinetics of carbamazepine and its epoxide metabolite using Monte Carlo simulation  

作　　者：Jun-jie DING Yun-jian ZHANG Zheng JIAO Yi WANG 

机构地区：[1]Children's Hospital of Fudan University,Shanghai 201102,China [2]Department of Pharmacy,Huashan Hospital of Fudan University,Shanghai 200040,China

出　　处：《Acta Pharmacologica Sinica》2012年第11期1431-1440,共10页中国药理学报（英文版）

基　　金：This study was supported by the National Natural Science Foundation of China （No 81072702 and No 81071116） and the major research and development project on innovative drugs, China Ministry of Science and Technology （2012ZX09303004- 001） The authors thank PhD candidates Mr Stephen Charles CROUCH and Miss Yu-zheng WANG （Albany College of Pharmacy and Health Sciences, NY, USA） for their critical reading and reviewing of the manuscript. The authors are also grateful to the anonymous reviewer for his valuable com- ments.

摘　　要：Aim： To study the effects of delayed and missed doses （poor compliance） on the pharmacokinetics of carbamazepine （CBZ） and its main active metabolite carbamazepine-10,11-epoxide （CBZE） in Chinese epilepsy patients using Monte Carlo simulation. Methods： CBZ and CBZE time-concentration profiles in various scenarios were generated based on a population pharmacokinetic study in Chinese epilepsy patients using Monte Carlo simulation. The scenarios included patients given multiple doses of CBZ that ranged from 100 to 300 mg three times daily or from 200 to 300 mg every 12 h. The therapeutic range of CBZ and CBZE for each scenario was estimated to assess the effect of delayed or missed doses and to design corresponding rescue regimens. Moreover, the impact of body weight, absorption rate and co-therapy with other antiepileptic drugs （phenytoin, phenobarbital and valproic acid） on the dosage recommendation was investigated in the event of poor compliance. Results： The risk for a sub-therapeutic range of CBZ and CBZE was increased in a dose-dependent manner in both two and three times daily regimens when delayed or missed doses occurred. The effects of poor compliance was less prominent on the lower daily doses compared with those on the higher daily doses. The dose recommendations, in the event of poor compliance, were time related and dose dependent. Patient body weight, absorption rate and co-therapy with phenytoin, phenobarbital and valproic acid had no significant impact on the dose recommendation. Conclusion; Patients with epilepsy should take the delayed doses as soon as they remember, and partial missed doses may need to be taken near or at the next scheduled time.Aim： To study the effects of delayed and missed doses （poor compliance） on the pharmacokinetics of carbamazepine （CBZ） and its main active metabolite carbamazepine-10,11-epoxide （CBZE） in Chinese epilepsy patients using Monte Carlo simulation. Methods： CBZ and CBZE time-concentration profiles in various scenarios were generated based on a population pharmacokinetic study in Chinese epilepsy patients using Monte Carlo simulation. The scenarios included patients given multiple doses of CBZ that ranged from 100 to 300 mg three times daily or from 200 to 300 mg every 12 h. The therapeutic range of CBZ and CBZE for each scenario was estimated to assess the effect of delayed or missed doses and to design corresponding rescue regimens. Moreover, the impact of body weight, absorption rate and co-therapy with other antiepileptic drugs （phenytoin, phenobarbital and valproic acid） on the dosage recommendation was investigated in the event of poor compliance. Results： The risk for a sub-therapeutic range of CBZ and CBZE was increased in a dose-dependent manner in both two and three times daily regimens when delayed or missed doses occurred. The effects of poor compliance was less prominent on the lower daily doses compared with those on the higher daily doses. The dose recommendations, in the event of poor compliance, were time related and dose dependent. Patient body weight, absorption rate and co-therapy with phenytoin, phenobarbital and valproic acid had no significant impact on the dose recommendation. Conclusion; Patients with epilepsy should take the delayed doses as soon as they remember, and partial missed doses may need to be taken near or at the next scheduled time.

关 键 词：CARBAMAZEPINE carbamazepine-10 11-epoxide COMPLIANCE Monte Carlo simulations nonlinear mixed effect model population pharmacokinetics therapeutic range 

分 类 号：TQ450.21[化学工程—农药化工] O242.2[理学—计算数学]