Aston Health Research Group, Aston Pharmacy School, Aston University, Birmingham B4 7ET, UK.
Aston Health Research Group, Aston Pharmacy School, Aston University, Birmingham B4 7ET, UK; Aston Pharmacy School, Aston University, Birmingham B4 7ET, UK.
J Pharm Sci. 2019 Jan;108(1):661-673. doi: 10.1016/j.xphs.2018.10.056. Epub 2018 Nov 3.
The insidious nature of Zika virus (ZIKV) infections can have a devastating consequence for fetal development. Recent reports have highlighted that chloroquine (CQ) is capable of inhibiting ZIKV endocytosis in brain cells. We applied pharmacokinetic modeling to develop a predictive model for CQ exposure to identify an optimal maternal/fetal dosing regimen to prevent ZIKV endocytosis in brain cells. Model validation used 13 nonpregnancy and 3 pregnancy clinical studies, and a therapeutic CQ plasma window of 0.3-2 μM was derived. Dosing regimens used in rheumatoid arthritis, systemic lupus erythematosus, and malaria were assessed for their ability to target this window. Dosing regimen identified that weekly doses used in malaria were not sufficient to reach the lower therapeutic window; however, daily doses of 150 mg achieved this therapeutic window. The impact of gestational age was further assessed and culminated in a final proposed regimen of 600 mg on day 1, 300 mg on day 2 and 3, and 150 mg thereafter until the end of trimester 2, which resulted in maintaining 65% and 94% of subjects with a trough plasma concentration above the lower therapeutic window on day 6 and at term, respectively.
寨卡病毒 (ZIKV) 感染的隐匿性质可能对胎儿发育造成毁灭性后果。最近的报告强调，氯喹 (CQ) 能够抑制脑细胞中的 ZIKV 内吞作用。我们应用药代动力学模型来开发 CQ 暴露的预测模型，以确定最佳的母体/胎儿给药方案，以防止脑细胞中的 ZIKV 内吞作用。模型验证使用了 13 项非妊娠和 3 项妊娠临床研究，并得出了治疗性 CQ 血浆窗为 0.3-2 μM。评估了类风湿关节炎、系统性红斑狼疮和疟疾中使用的给药方案，以确定其靶向该窗口的能力。确定疟疾中使用的每周剂量不足以达到较低的治疗窗；然而，每日 150 毫克的剂量达到了这一治疗窗。进一步评估了妊娠期的影响，最终提出了一个方案：第 1 天给予 600 毫克，第 2 天和第 3 天给予 300 毫克，此后每天给予 150 毫克，直到妊娠第 2 期末，这使得 65%和 94%的受试者在第 6 天和足月时的谷浓度保持在较低的治疗窗之上。
