University of California, San Diego, La Jolla, California, USA.
Clin Pharmacol Ther. 2012 Feb;91(2):243-9. doi: 10.1038/clpt.2011.218. Epub 2011 Dec 21.
Improved antiretroviral therapies are needed for the treatment of HIV-infected infants, given the rapid progression of the disease and drug resistance resulting from perinatal exposure to antiretrovirals. We examined longitudinal pharmacokinetics (PK) data from a clinical trial of lopinavir/ritonavir (LPV/r) in HIV-infected infants in whom therapy was initiated at less than 6 months of age. A population PK analysis was performed using NONMEM to characterize changes in lopinavir (LPV) PK relating to maturational changes in infants, and to assess dosing requirements in this population. We also investigated the relationship between LPV PK and viral dynamic response. Age and ritonavir concentrations were the only covariates found to be significant. Population PK of LPV was characterized by high apparent clearance (CL/F) in young infants, which decreased with increasing age. Although younger infants had lower LPV concentrations, the viral dynamics did not correlate with initial LPV exposure. Monte Carlo simulations demonstrated that WHO weight band-based dosing recommendations predicted therapeutic LPV concentrations and provided drug exposure levels comparable to those resulting from US Food and Drug Administration (FDA)-suggested dosing regimens.
鉴于艾滋病病毒感染婴儿疾病的快速进展以及围产期接触抗逆转录病毒药物导致的耐药性，需要改进抗逆转录病毒疗法。我们检查了在接受不到 6 个月龄时开始治疗的艾滋病病毒感染婴儿中洛匹那韦/利托那韦 (LPV/r) 临床试验的纵向药代动力学 (PK) 数据。采用 NONMEM 进行群体 PK 分析，以描述与婴儿成熟变化相关的洛匹那韦 (LPV) PK 变化，并评估该人群的剂量需求。我们还研究了 LPV PK 与病毒动力学反应之间的关系。年龄和利托那韦浓度是唯一被发现具有显著意义的协变量。LPV 的群体 PK 表现为年幼婴儿的表观清除率 (CL/F) 较高，随着年龄的增长而降低。尽管年幼婴儿的 LPV 浓度较低，但病毒动力学与初始 LPV 暴露无关。蒙特卡罗模拟表明，基于世界卫生组织体重带的剂量建议预测了治疗性 LPV 浓度，并提供了与美国食品和药物管理局 (FDA) 建议剂量方案相当的药物暴露水平。
