Empiric dosing strategies to predict lamotrigine concentrations during pregnancy.
Empiric dosing strategies to predict lamotrigine concentrations during pregnancy.
复制标题
预测妊娠期间拉莫三嗪浓度的经验剂量策略。
DOI：
10.1002/phar.2856
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发表时间：
2023
期刊：
影响因子：
4.1
通讯作者：
Birnbaum,AngelaK
中科院分区：
文献类型：
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作者：
Barry,JessicaM;French,JacquelineA;Pennell,PageB;Karanam,Ashwin;Harden,CynthiaL;Birnbaum,AngelaK
用拉莫三嗪维持癫痫发作控制是复杂的，药代动力学的改变和妊娠期间清除量增加或保持不变的亚群的存在。目的我们的目的是表征特定给药情景导致癫痫发作风险或毒性增加的可能性。方法将我们先前研究获得的拉莫三嗪药代动力学参数应用于一个一室模型结构，其中亚群(75：25%)呈现不同的清除量变化。用来自每个亚群的典型药代动力学参数值进行单患者模拟。人群水平模拟(N= 48,000)包括六种剂量方案，并使用R包mrgsolve(Metrum研究小组)考虑了四种先入性剂量。结果单独模拟结果显示，在不增加剂量的情况下，高清除改变(HC)亚群的药物浓度在6-8 周时降至0.65以下，这取决于先前的清除。虽然没有模拟剂量方案允许两个亚群中的所有女性保持先入为主的浓度，但一些方案提供了比其他方案更平衡的风险概况。预测的浓度显示，HC组中7%-100%的女性癫痫发作风险潜在增加，这取决于先孕剂量和亚群。此外，在63%的低清除变化(LC)女性的剂量方案中，毒性风险增加(34%-100%)。有意义相当大比例的模拟个体的浓度低到足以增加癫痫风险或高到足以产生毒性。早期清除变化表明，如果在怀孕前三个月进行治疗药物监测，可能会进行亚群分类。一种武断的“一刀切”的理念可能不适用于妊娠期间拉莫三嗪的剂量调整，并强化了在确定患者属于LC或HC组之前进行治疗药物监测的必要性。
IntroductionMaintaining seizure control with lamotrigine is complicated by altered pharmacokinetics and existence of subpopulations in whom clearance increases or remains constant during pregnancy.ObjectiveOur objective was to characterize the potential for particular dosing scenarios to lead to increased seizure risk or toxicity.MethodsLamotrigine pharmacokinetic parameters obtained from our previous study were applied to a one‐compartment model structure with subpopulations (75:25%) exhibiting different clearance changes. A single‐patient simulation was conducted with typical pharmacokinetic parameter values from each subpopulation. Population‐level simulations (N= 48,000) included six dosing scenarios and considered four preconception doses using the R package mrgsolve (Metrum Research Group). Thresholds for efficacy and toxicity were selected as drug concentration that are 65% lower than preconception concentrations and doubling of preconception concentrations, respectively.ResultsIndividual simulation results demonstrated that without dose increases, concentrations fell below 0.65 at 6–8 weeks in the high clearance change (HC) subpopulation, depending on preconception clearance. While no simulated dosing regimen allowed all women in both subpopulations to maintain preconception concentrations, some regimens provided a more balanced risk profile than others. Predicted concentrations suggested potential increased seizure risk for 7%–100% of women in the HC group depending on preconception dose and subpopulation. Additionally, in 63% of dosing scenarios for women with low clearance change (LC), there was an increased risk of toxicity (34%–100% of women).SignificanceA substantial percentage of simulated individuals had concentrations low enough to potentially increase seizure risk or high enough to create toxicity. Early clearance changes indicate possible subpopulation categorization if therapeutic drug monitoring is conducted in the first trimester. An arbitrary “one‐size‐fits‐all” philosophy may not work well for lamotrigine dosing adjustments during pregnancy and reinforces the need for therapeutic drug monitoring until a patient is determined to be in the LC or HC group.