论文部分内容阅读
目的根据药动/药效(PK/PD)理论应用蒙特卡洛模拟评价和优化拉莫三嗪的儿童给药方案。方法依据已发表的拉莫三嗪儿童群体药动学研究资料,分别评估拉莫三嗪在21种给药方案下各运行蒙特卡洛模拟10 000例次可能达到的稳态血药浓度(css)值及其概率分布,进而找出拉莫三嗪在2~12岁患儿中的最优维持给药方案。结果拉莫三嗪单药治疗(2.5 mg·kg-1·次-1,bid)、拉莫三嗪(1.0 mg·kg-1·次-1,bid)+丙戊酸、拉莫三嗪(3.5 mg·kg-1·次-1,bid)+酶诱导剂、拉莫三嗪(2.0 mg·kg-1·次-1,bid)+丙戊酸+酶诱导剂方案下患儿css分布于治疗窗(2.5~15.0 mg·L-1)内的中靶概率(PTA)最高,分别为89.21%、76.61%、76.03%和81.22%,且css高于治疗窗的PTA最小,分别为7.78%、9.97%、8.00%和9.73%,上述为最优给药方案。拉莫三嗪单药治疗(10.0 mg·kg-1·d-1)、拉莫三嗪(5.0 mg·kg-1·d-1)+丙戊酸、拉莫三嗪(15.0 mg·kg-1·d-1)+酶诱导剂和拉莫三嗪(10.0 mg·kg-1·d-1)+丙戊酸+酶诱导剂方案下css高于治疗窗的PTA>40%,超过上述剂量不应推荐。敏感性分析表明在排除给药剂量的影响后,合并用药是影响拉莫三嗪稳态血药浓度的主要因素。结论本研究应用蒙特卡洛模拟评价了拉莫三嗪在不同给药方案下的安全性和有效性,拟合结果可为临床合理用药提供参考。
Objective To evaluate and optimize the dosage regimen of lamotrigine according to the pharmacokinetic / pharmacodynamic (PK / PD) theory using Monte Carlo simulation. Methods Based on published data on pharmacokinetics of lamotrigine in children, we evaluated the steady-state plasma concentrations of lamotrigine that could be achieved in each of 10 000 Monte Carlo simulation runs under 21 dosing schedules (css ) Values and their probability distribution, and then find the optimal maintenance dosing regimen of lamotrigine in children aged 2 to 12 years. RESULTS: Lamotrigine alone (2.5 mg · kg -1 · d -1 bid), lamotrigine (1.0 mg · kg -1 · d -1 bid) + valproic acid, lamotrigine (3.5 mg · kg -1 · d -1 bid) + enzyme inducer, lamotrigine (2.0 mg · kg -1 · d -1 bid) + valproic acid + enzyme inducer The highest target probability (PTA) was 89.21%, 76.61%, 76.03% and 81.22% respectively in the treatment window (2.5-15.0 mg · L-1), and the PTA was the lowest in the treatment window 7.78%, 9.97%, 8.00% and 9.73%, respectively. The above is the optimal dosage regimen. Lamotrigine monotherapy (10.0 mg · kg -1 · d -1), lamotrigine (5.0 mg · kg -1 · d -1) + valproic acid, lamotrigine (15.0 mg · kg -1) -1 · d-1) + enzyme inducer and lamotrigine (10.0 mg · kg-1 · d-1) + valproic acid + enzyme inducing agent css higher than the therapeutic window PTA> 40% The above dose should not be recommended. Sensitivity analysis showed that after excluding the effect of dose, the combination of medication is the main factor affecting the steady-state plasma concentration of lamotrigine. Conclusions This study evaluated the safety and efficacy of lamotrigine under different dosing regimens using Monte Carlo simulation. The results of the fitting could provide a reference for clinical rational drug use.