Dalla Rosa Gisela Myrian de Lima Leite, Yamamoto Priscila Akemi, Melo Maria Madalena Corrêa, Sakamoto Gustavo F, Montanha Maiara C, Paixão Paulo, Diniz Andréa, de Moraes Natália Valadares, Kimura Elza
Regional University Hospital of Maringá, Pharmacy, State University of Maringá, Maringá, Paraná, Brazil.
Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
J Antimicrob Chemother. 2025 Jul 1;80(7):1893-1901. doi: 10.1093/jac/dkaf144.
To characterize the impact of obesity and Roux-en-Y gastric bypass (RYGB) on systemic exposure to amoxicillin using population modeling approach. We also performed simulations to provide insights into optimising the dosing of amoxicillin against infectious bacteria in the respiratory tract.
Non-obese, obese, and post-RYGB patients, aged between 24 and 50 years, from two clinical studies, were evaluated. Sex, age, body size descriptors, history of bariatric surgery and renal function were assessed as potential covariates. The percentage of time of unbound amoxicillin plasma concentration above the minimum inhibitory concentration (%fT > MIC) of >40%, representing bactericidal activity, was used as a PK/PD target to calculate the probability of target attainment (PTA). The PTA threshold was defined as 90% of treated individuals achieving fT > MIC ≥ 40%.
Amoxicillin PK was best characterized by a one-compartment model including a zero-order absorption with lag time followed by a first-order absorption and linear elimination. The relative oral bioavailability in post-RYGB patients was nearly halved compared with non-obese subjects. Age exhibited a negative correlation with clearance, consistent with amoxicillin being a hydrophilic drug primarily eliminated through the kidneys. For MIC ≤ 2 mg/L, the oral dosing regimen of 1000 mg q6h reached the therapeutic target for non-obese. For MIC ≤ 1 mg/L, 1000 mg q6h is needed in obese and post-RYGB subjects.
Amoxicillin doses of 1000 mg q6h were found to maximize the probability of attaining the PK/PD target with MIC ≤ 1 mg/L in obese and post-RYGB patients.
采用群体建模方法，描述肥胖症和Roux-en-Y胃旁路术（RYGB）对阿莫西林全身暴露的影响。我们还进行了模拟，以深入了解优化阿莫西林针对呼吸道感染细菌的给药方案。
评估了来自两项临床研究的年龄在24至50岁之间的非肥胖、肥胖和RYGB术后患者。将性别、年龄、身体尺寸描述符、减肥手术史和肾功能作为潜在协变量进行评估。游离阿莫西林血浆浓度高于最低抑菌浓度（%fT＞MIC）且＞40%的时间百分比，代表杀菌活性，用作药代动力学/药效学（PK/PD）靶点，以计算达到靶点的概率（PTA）。PTA阈值定义为90%的治疗个体实现fT＞MIC≥40%。
阿莫西林的药代动力学最好用单室模型来描述，该模型包括零级吸收并伴有滞后时间，随后是一级吸收和线性消除。与非肥胖受试者相比，RYGB术后患者的相对口服生物利用度几乎减半。年龄与清除率呈负相关，这与阿莫西林是一种主要通过肾脏消除的亲水性药物一致。对于MIC≤2mg/L，非肥胖者每6小时口服1000mg的给药方案达到了治疗靶点。对于MIC≤1mg/L，肥胖和RYGB术后受试者需要每6小时口服1000mg。
发现每6小时口服1000mg阿莫西林的剂量可使肥胖和RYGB术后患者在MIC≤1mg/L时达到PK/PD靶点的概率最大化。
