Antiretroviral Pharmacology/Lactating Mother/Infants

描述（由申请人提供）：发展中国家的许多感染艾滋病毒的哺乳期母亲现在正在接受抗逆转录病毒药物（ARV）以维持自身健康，并在临床试验中预防母乳艾滋病毒传播。虽然初步数据表明，迄今为止测试的所有抗逆转录病毒药物都存在于母乳中，但这些数据不足以准确确定母乳中的婴儿药物剂量和婴儿药物暴露量。这些作用可能是有益的，例如保护未感染的婴儿免受母乳中的HIV感染，或不利的，例如在感染的婴儿中产生抗ARV病毒株或慢性ARV暴露的药物毒性。作为临床护理或研究方案的一部分，在抗逆转录病毒药物可以安全地用于哺乳母亲之前，需要对婴儿母乳抗逆转录病毒药物剂量和药物暴露进行定量了解。母乳与母体血浆药物或血清浓度的比值不是恒定的，从随机时间点的该比值测定结果进行外推是不可靠的，可能会产生误导。在大多数环境中，对哺乳母亲及其婴儿进行更密集的抽样是不切实际的。该项目提出了一种新颖的和创新的方法，使用稀疏采样和群体药代动力学建模。将测量采用稀疏采样策略采集的母体血浆、母乳和婴儿滤纸样本中齐多夫定（ZDV）、拉米夫定（3 TC）和奈韦拉平（NVP）的浓度。这些数据将用于开发母体血液、母乳和婴儿血液中ZDV、3 TC和NVP药代动力学的群体模型，并描述母体ZDV/3 TC/NVP治疗期间婴儿从母乳中的全身ARV暴露。涉及群体建模的药代动力学方法以前从未用于描述母乳药物转移和暴露。该项目中提出的创新方法可以作为一种有效和实用的方法来研究母乳中所有药物转移的程度和影响的模式。该项目将使用一种新的分析方法来描述母乳中的抗逆转录病毒药物从接受抗逆转录病毒治疗的艾滋病毒感染母亲转移到其哺乳期婴儿。这些信息是需要在哺乳期妇女中安全有效地使用抗逆转录病毒药物，并将开创一种新的方法来研究母乳药物转移。

DESCRIPTION (provided by applicant): Many HIV infected nursing mothers in the developing world are now receiving antiretrovirals (ARV's) for maintenance of their own health and in clinical trials for prevention of breast milk HIV transmission. While preliminary data demonstrate that all ARV's tested to date are present in breast milk, this data is inadequate to accurately determine infant drug dose from breast milk and infant drug exposure from that dose. These effects may be beneficial, such as protection of uninfected infants from infection by HIV in breast milk, or adverse, such as the development of ARV resistant viral strains in infected infants or drug toxicity from chronic ARV exposure. A quantitative understanding of infant breast milk ARV dose and drug exposure is required before ARV's can be used safely in nursing mothers as part of clinical care or research protocols. The ratio of breast milk to maternal plasma drug or serum concentrations is not constant, and extrapolation from determinations of this ratio at random time points is unreliable and may be misleading. More intensive sampling of nursing mothers and their infants is not practical in most environments. This project proposes a novel and innovative approach using sparse sampling and population pharmacokinetic modeling. Concentrations of zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) will be measured in maternal plasma, breast milk and infant filter paper samples collected with a sparse sampling strategy. This data will be used to develop population models of ZDV, 3TC and NVP pharmacokinetics in maternal blood, breast milk and infant blood and to describe infant systemic ARV exposure from breast milk during maternal ZDV/3TC/NVP therapy. A pharmacokinetic approach involving population modeling has never before been used to describe breast milk drug transfer and exposure. The innovative approach proposed in this project can serve as a model for an efficient and practical way to study the extent and effects of transfer of all drugs in breast milk. This project will use a new analytic approach to describe transfer of antiretrovirals in breast milk from HIV infected mothers receiving antiretroviral therapy to their nursing infants. This information is needed for the safe and effective use of antiretrovirals in nursing women, and will pioneer a novel approach to the study of breast milk drug transfer.