College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Pharmacotherapy. 2024 Jan;44(1):77-86. doi: 10.1002/phar.2878. Epub 2023 Sep 29.
Cefazolin is the leading antibiotic used to prevent surgical site infections worldwide. Consensus guidelines recommend adjustment of the cefazolin dose above and below 120 kg without regard to body composition. Algorithms exist to repurpose radiologic data into body composition (morphomics) and inform dosing decisions in obesity.
To compare the current standard of body weight to morphomic measurements as covariates of cefazolin pharmacokinetics and aid dose stratification of cefazolin in patients with obesity undergoing colorectal surgery.
This prospective study measured cefazolin plasma, fat, and colon tissue concentrations in colorectal surgery patients in order to develop a morphomics-informed population pharmacokinetic (PopPK) model to guide dose adjustments. A physiologically-based pharmacokinetic (PBPK) model was also constructed to inform tissue partitioning in morbidly obese patients (n = 21, body mass index ≥35 kg/m with one or more co-morbid conditions).
Morphomics and pharmacokinetic data were available in 58 patients with a median [min, max] weight and age of 95.9 [68.5, 148.8] kg and 55 [25, 79] years, respectively. The plasma-to-subcutaneous fat partition coefficient was predicted to be 0.072 and 0.060 by the PopPK and PBPK models, respectively. The estimated creatinine clearance (eCL ) and body depth at the third lumbar vertebra (body depth_L3) were identified as covariates of cefazolin exposure. The probability of maintaining subcutaneous fat concentrations above 2 μg/mL for 100% of a 4-h surgical period was below 90% when eCLcr ≥105 mL/min and body depth_L3 ≥ 300 mm and less sensitive to the rate of infusion between 5 and 60 min.
Kidney function and morphomics were more informative than body weight as covariates of cefazolin target site exposure. Data from more diverse populations, consensus on target cefazolin exposure, and comparative studies are needed before a change in practice can be implemented.
头孢唑林是全球用于预防手术部位感染的主要抗生素。共识指南建议在不考虑身体成分的情况下，调整头孢唑林剂量高于或低于 120kg。存在将放射学数据转化为身体成分（形态组学）并为肥胖患者的给药决策提供信息的算法。
比较当前体重标准与形态组学测量值作为肥胖患者接受结直肠手术时头孢唑林药代动力学的协变量，并辅助头孢唑林的剂量分层。
本前瞻性研究测量了结直肠手术患者的头孢唑林血浆、脂肪和结肠组织浓度，以开发形态组学指导的群体药代动力学（PopPK）模型，指导剂量调整。还构建了生理基础药代动力学（PBPK）模型，以告知病态肥胖患者（BMI≥35kg/m 且有一个或多个合并症）的组织分配。
形态组学和药代动力学数据可用于 58 例患者，中位（最小，最大）体重和年龄分别为 95.9[68.5，148.8]kg 和 55[25，79]岁。PopPK 和 PBPK 模型分别预测血浆与皮下脂肪的分配系数为 0.072 和 0.060。估计的肌酐清除率（eCL）和第三腰椎的身体深度（body depth_L3）被确定为头孢唑林暴露的协变量。当 eCLcr≥105mL/min 且 body depth_L3≥300mm 时，100%的 4 小时手术期间维持皮下脂肪浓度高于 2μg/mL 的概率低于 90%，并且对 5 至 60 分钟之间的输注速度不敏感。
肾功能和形态组学比体重作为头孢唑林靶部位暴露的协变量更具信息性。在实施实践改变之前，需要更多来自不同人群的数据、对目标头孢唑林暴露的共识以及比较研究。
