A Pharmacokinetic Dose-Optimization Study of Cabotegravir and Bictegravir in a Mouse Pregnancy Model.
A Pharmacokinetic Dose-Optimization Study of Cabotegravir and Bictegravir in a Mouse Pregnancy Model.
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DOI：
10.3390/pharmaceutics14091761
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发表时间：
2022-08-24
期刊：
影响因子：
5.4
通讯作者：
Serghides, Lena
中科院分区：
文献类型：
--
作者：
Mohan, Haneesha;Atkinson, Kieran;Watson, Birgit;Brumme, Chanson J.;Serghides, Lena
关键词：
动物妊娠模型可以成为研究HIV抗逆转录病毒安全性和毒性以及进行不易在人类中进行的机制研究的有用工具。在这些模型中使用临床相关剂量可提高结果的相关性。Cabotegravir和bictegravir是新的整合酶链转移抑制剂（INSTIs），最近被批准用于治疗艾滋病毒感染者。这些药物在妊娠期的研究非常有限。本研究的目的是在小鼠妊娠模型中进行cabotegravir和bictegravir的剂量优化研究，目的是确定产生与人体中观察到的血浆药物浓度相似的血浆药物浓度的剂量。从妊娠第11.5天至第15.5天，通过口服管饲法向妊娠小鼠施用递增剂量的卡替拉韦或比替拉韦与恩曲他滨和替诺福韦的组合。使用高效液相色谱-串联质谱法测定给药后1 h和24 h母体血浆中的药物浓度以及给药后1 h羊水中的药物浓度。还报告了cabotegravir和bictegravir人体药代动力学研究的综述。我们希望这些数据将鼓励在动物妊娠模型中进行HIV抗逆转录病毒安全性/毒性研究和机制研究。
Animal pregnancy models can be useful tools to study HIV antiretroviral safety and toxicity and to perform mechanistic studies that are not easily performed in humans. Utilization of clinically relevant dosing in these models improves the relevance of the findings. Cabotegravir and bictegravir are new integrase strand transfer inhibitors (INSTIs), recently approved for the treatment of people living with HIV. Studies of these drugs in pregnancy are very limited. The objective of this study was to perform a dose-optimization study of cabotegravir and bictegravir in a mouse pregnancy model with the goal of determining the dose that would yield plasma drug concentrations similar those observed in humans. Pregnant mice were administered increasing doses of cabotegravir or bictegravir in combination with emtricitabine and tenofovir by oral gavage from gestational day 11.5 to 15.5. Drug concentrations in the maternal plasma at 1 h and 24 h post drug administration and in the amniotic fluid at 1 h post drug administration were determined using high-performance liquid chromatography coupled with tandem mass spectrometry. A review of cabotegravir and bictegravir human pharmacokinetic studies are also reported. We hope these data will encourage studies of HIV antiretroviral safety/toxicity and mechanistic studies in animal pregnancy models.
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DOI：
10.1126/science.1248707
发表时间：
2014-03-07
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
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影响因子：
16.1
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DOI：
10.1093/infdis/jiu393
发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
Serghides L