Rubino Christopher M, Van Wart Scott A, Bhavnani Sujata M, Ambrose Paul G, McCollam Jill S, Forrest Alan
Institute for Clinical Pharmacodynamics, Ordway Research Institute, Inc., Albany, New York, USA.
Antimicrob Agents Chemother. 2009 Oct;53(10):4422-8. doi: 10.1128/AAC.00231-09. Epub 2009 Jul 27.
Oritavancin is a novel glycopeptide antimicrobial agent with potent in vitro activity against a wide variety of gram-positive bacteria, including multidrug-resistant strains of staphylococci and enterococci. A population pharmacokinetic model was developed to describe the disposition of oritavancin with data from a pooled population of phase 1 healthy subjects and phase 2 and 3 patients with complicated skin and skin structure infections or Staphylococcus aureus bacteremia. In addition, the potential influence of factors such as the subject's age, gender, and clinical laboratory measures on oritavancin disposition was evaluated. Oritavancin was administered as both single- and multiple-dose intravenous (i.v.) infusions in fixed doses ranging from 100 to 800 mg or weight-based doses ranging from 0.02 to 10 mg/kg of body weight, with infusion durations ranging from 0.13 to 6.5 h across all studies. The most robust fit to the data (n = 6,290 oritavancin plasma concentrations from 560 subjects) was obtained using a three-compartment model with zero-order i.v. infusion and first-order elimination. The model was parameterized using total clearance (CL), volume of central compartment (Vc), distributional clearances from the central to both the first and second peripheral compartments, and volumes of distribution for both the first and second peripheral compartments. Weight and study phase (phase 1 versus phase 2/3) were identified as significant predictors of the interindividual variability in CL, while body surface area and age were significant for Vc. These results suggest that dose modification may be warranted in patients weighing >110 kg. However, the mild nature of the observed relationships for Vc suggest that dosing adjustments are not necessary for elderly patients.
奥利万星是一种新型糖肽类抗菌剂，对多种革兰氏阳性菌具有强大的体外活性，包括葡萄球菌和肠球菌的多重耐药菌株。利用来自1期健康受试者以及2期和3期患有复杂皮肤及皮肤结构感染或金黄色葡萄球菌菌血症患者的汇总群体数据，建立了群体药代动力学模型来描述奥利万星的处置情况。此外，还评估了受试者年龄、性别和临床实验室指标等因素对奥利万星处置的潜在影响。在所有研究中，奥利万星均以100至800毫克的固定剂量或0.02至10毫克/千克体重的基于体重的剂量进行单剂量和多剂量静脉输注，输注持续时间为0.13至6.5小时。使用具有零级静脉输注和一级消除的三室模型获得了对数据（来自560名受试者的6290个奥利万星血浆浓度）的最稳健拟合。该模型使用总清除率（CL）、中央室容积（Vc）、从中央室到第一和第二外周室的分布清除率以及第一和第二外周室的分布容积进行参数化。体重和研究阶段（1期与2/3期）被确定为CL个体间变异性的显著预测因素，而体表面积和年龄对Vc有显著影响。这些结果表明，体重>110千克的患者可能需要调整剂量。然而，观察到的Vc关系性质较轻，表明老年患者无需调整剂量。
