AP-HP, Tropical and Infectious Diseases department, Hôpital Saint-Louis, Paris, France.
CIC-EC 1425, INSERM, F-75018 Paris, France.
J Antimicrob Chemother. 2020 Dec 1;75(12):3611-3618. doi: 10.1093/jac/dkaa368.
Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav.
Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC-tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix.
Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT>MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral).
Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.
肺炎、皮肤和软组织感染在肥胖患者中更为常见，通常使用复方阿莫西林克拉维酸进行治疗，用药剂量与非肥胖患者相似。目前尚无肥胖患者接受复方阿莫西林克拉维酸治疗时阿莫西林药代动力学的数据。
本研究为前瞻性、单中心、开放标签、非随机、交叉药代动力学试验，纳入了肥胖但健康的成年受试者。受试者首先静脉输注复方阿莫西林克拉维酸（阿莫西林/克拉维酸 1000/200mg）30 分钟，然后口服给予第二剂（阿莫西林 1000/125mg），两次给药之间有≥24 小时的洗脱期。我们采用经验证的超高效液相色谱-串联质谱技术检测阿莫西林的浓度。我们采用 Monolix 开发的 SAEM 算法通过非线性混合效应模型估算阿莫西林的群体药代动力学参数。
27 名受试者纳入静脉研究，其中 24 名纳入口服部分研究。受试者的中位体重和 BMI 分别为 109.3kg 和 40.6kg/m2。阿莫西林药代动力学最好用具有一级消除的两室模型来描述。阿莫西林的清除率、中央容积、隔室间清除率和外周容积的平均值分别为 14.6L/h、9.0L、4.2L/h 和 6.4L。阿莫西林的口服生物利用度为 79.7%。口服给药后阿莫西林的 Cmax 随体重显著降低（P=0.013）。阿莫西林剂量模拟预测，对于 MIC 滴定至 0.5mg/L（静脉）和 1mg/L（口服）的方案，大多数人群将通过使用复方阿莫西林克拉维酸 1000/200mg（静脉）或 1000/125mg（口服）q8h 实现 fT>MIC≥40%的药效学目标。
肥胖患者可以获得阿莫西林的药代动力学/药效学目标。
