Badhan Raj K S, Macfarlane Hannah
Medicines Optimisation Research Group, Aston Pharmacy School, Aston University, Birmingham, UK.
J Pharm Pharmacol. 2020 May;72(5):670-681. doi: 10.1111/jphp.13236. Epub 2020 Feb 3.
The second-generation antipsychotic quetiapine has been demonstrated to undergo gestation-related changes in pharmacokinetics. This study applied pharmacokinetic modelling principles to investigate the mechanism of these changes and to propose new dosing strategies to counteract these changes.
A pharmacokinetic modelling approach was implemented using virtual population groups. Changes in quetiapine trough plasma concentration during gestation were quantified across all trimesters, and dose adjustment strategies were applied to counteract these changes by targeting a therapeutic range of 50-500 ng/ml throughout gestation.
The application of the model during gestation predicted a decrease in trough concentration. A maximum decrease of 58% was predicted during trimester 2, and being associated with a statistically significant decrease in oral clearance at gestation week 25, 204 l/h ± 100.8 l/h compared with non-pregnant subjects, 121.9 l/h ± 51.8 l/h. A dosing optimisation strategy identified that dose increases to 500-700 mg twice daily would result in 32-55% of subjects possessing trough concentration in excess of 50 ng/ml.
Quetiapine doses in pregnancy should be increased to 500-700 mg twice daily to counteract a concomitant increase in metabolic clearance, increase in volume of distribution and decrease in plasma protein binding.
第二代抗精神病药物喹硫平已被证明在妊娠期药代动力学发生与妊娠相关的变化。本研究应用药代动力学建模原理来研究这些变化的机制，并提出新的给药策略以抵消这些变化。
采用虚拟人群组实施药代动力学建模方法。对整个孕期喹硫平谷浓度的变化进行量化，并应用剂量调整策略，通过在整个孕期将治疗范围设定为50 - 500 ng/ml来抵消这些变化。
该模型在妊娠期的应用预测谷浓度会降低。预测在妊娠中期谷浓度最大降低58%，且与妊娠第25周时口服清除率的统计学显著降低相关，与非妊娠受试者相比，妊娠第25周时口服清除率为204 l/h ± 100.8 l/h，而非妊娠受试者为121.9 l/h ± 51.8 l/h。一种给药优化策略确定，每日两次将剂量增加至500 - 700 mg会使32% - 55%的受试者谷浓度超过50 ng/ml。
妊娠期喹硫平剂量应增加至每日两次500 - 700 mg，以抵消代谢清除率增加、分布容积增加和血浆蛋白结合率降低的影响。
