Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women.
Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women.
复制标题
孕妇经肾排泄抗逆转录病毒药物的基于生理学的药代动力学模型。
DOI：
10.1111/bcp.12685
复制
发表时间：
2015
影响因子：
3.4
通讯作者：
S. Benaboud
中科院分区：
文献类型：
--
作者：
M. De Sousa Mendes;D. Hirt;S. Urien;Elodie Valade;N. Bouazza;F. Foissac;S. Blanche;J. Treluyer;S. Benaboud
目的
妊娠期间的生理变化会影响药物处置。预测这些变化将有助于最大限度地提高孕妇的药物疗效和安全性。我们的目的是确定生理药代动力学（PBPK）是否可以准确预测妊娠期间肾排泄抗逆转录病毒药物的处置变化。
方法
建立了替诺福韦（TFV）、恩曲他滨（FTC）和拉米夫定（3 TC）三种经肾排泄的抗逆转录病毒药物的全身PBPK模型。为了评估妊娠对PK的影响，使用了p-PBPK Simcyp软件包中可用的时变妊娠相关生理参数。妊娠期间肾清除率随肾小球滤过率变化而变化，伴有或不伴有分泌变化。模拟PK曲线，并与观察到的数据进行比较，即曲线下面积（AUC）、血浆峰浓度（Cmax）和口服清除率（CL/F）。
结果
PBPK模型成功预测了非妊娠和妊娠人群的TFV、FTC和3 TC处置。妊娠期间肾脏分泌和滤过功能均发生变化。肾清除分泌的变化与肾血浆流量的变化有关。最大清除率增加约为30%（TFV 33%，FTC 31%，3 TC 29%）。
结论
妊娠期PBPK模型是量化妊娠期经肾排泄药物暴露量变化的有用工具。这些模型可用于评估替代给药方案，以优化妊娠期间的药物治疗。
AIM
Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy.
METHODS
Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (Cmax ) and oral clearances (CL/F).
RESULTS
PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%).
CONCLUSIONS
Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy.
DOI：
10.1124/jpet.301.1.145
发表时间：
2002-04-01
影响因子：
3.5
作者：
Buist, SCN;Cherrington, NJ;Klaassen, CD
通讯作者：
Klaassen, CD