Model-Based Analysis of Unbound Lopinavir Pharmacokinetics in HIV-Infected Pregnant Women Supports Standard Dosing in the Third Trimester.
Model-Based Analysis of Unbound Lopinavir Pharmacokinetics in HIV-Infected Pregnant Women Supports Standard Dosing in the Third Trimester.
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DOI：
10.1002/psp4.12065
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Dumond JB
中科院分区：
文献类型：
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作者：
Chen J;Malone S;Prince HM;Patterson KB;Dumond JB
妊娠期间的生理变化会影响药物的药代动力学。本文提出一个群体药代动力学模型来描述未结合洛匹那韦/利托那韦（LPV/RTV）PK参数随胎龄的纵向变化，并预测不同给药方案下未结合LPV浓度。妊娠期间LPV和RTV表观固有清除率的变化用胎龄的指数函数描述。LPV/RTV的未结合分数在妊娠期和产后无显著差异。模拟显示，尽管LPV固有清除率增加，但使用标准剂量（400/100 mg b.i.d.）在>90%的模拟中，病毒IC 50增加≤4倍。随着病毒易感性的降低，更高的剂量增加了有效性的可能性。当IC 50增加≥40倍时，IQ提示应考虑替代方案。该方法完善了先前的LPV PK报告，并支持标准剂量对易感病毒有效。
Physiological changes during pregnancy can affect drug pharmacokinetics. Here we present a population pharmacokinetic model to describe the longitudinal change of unbound lopinavir/ritonavir (LPV/RTV) PK parameters with gestational age, and to predict unbound LPV concentrations under different dosing regimens. The changes in apparent intrinsic clearances of LPV and RTV during pregnancy are described using an exponential function of gestational age. The unbound fractions of LPV/RTV are not significantly different between pregnancy and postpartum. Simulation reveals that despite increases in LPV intrinsic clearance, effective LPV inhibitory quotient (IQ) values are predicted with the standard dosing (400/100 mg b.i.d.) in >90% of simulations, with ≤4‐fold increase in viral IC50. As viral susceptibility decreases, higher doses increase the likelihood of efficacy. With ≥40‐fold increases in IC50, IQs suggest alternate regimens be considered. This approach refines previous LPV PK reports, and supports that standard dosing is effective with susceptible virus.