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Penetration of Vancomycin into Noninfected Bone in Patients Undergoing Total Joint Arthroplasty Evaluated by a Minimal Physiologically Based Population Pharmacokinetic Modeling Approach

万古霉素 药代动力学 医学 假体周围 人口 关节置换术 外科 内科学 金黄色葡萄球菌 遗传学 生物 环境卫生 细菌
作者
Cornelia B. Landersdorfer,Wee Leng Lee,Roger L. Nation,David C. M. Kong,Kirsty Buising,Trisha Peel,Peter Choong
出处
期刊:Molecular Pharmaceutics [American Chemical Society]
卷期号:20 (3): 1509-1518
标识
DOI:10.1021/acs.molpharmaceut.2c00724
摘要

Arthroplasty is a healthcare priority and represents high volume, high cost surgery. Periprosthetic joint infection (PJI) results in significant mortality, thus it is vital that the risk for PJI is minimized. Vancomycin is recommended for surgical prophylaxis in total joint arthroplasty (TJA) by current clinical practice guidelines endorsed by the Infectious Diseases Society of America. This study aimed to develop a new assay to determine vancomycin concentrations in serum and bone, and a minimal physiologically based population PK (mPBPK) model to evaluate vancomycin bone penetration in noninfected patients. Eleven patients undergoing TJA received 0.5–2.0 g intravenous vancomycin over 12–150 min before surgery. Excised bone specimens and four blood samples were collected per patient. Bone samples were pulverized under liquid nitrogen using a cryogenic mill. Vancomycin concentrations in serum and bone were analyzed by liquid chromatography-tandem mass spectrometry and subjected to mPBPK modeling. Vancomycin serum and bone concentrations ranged from 9.30 to 86.6 mg/L, and 1.94–37.0 mg/L, respectively. Average bone to serum concentration ratio was 0.41 (0.16–1.0) based on the collected samples. The population mean total body clearance was 2.12L/h/kg0.75. Inclusion of total body weight as a covariate substantially decreased interindividual variability in clearance. The bone/blood partition coefficient (Kpbone) was estimated at 0.635, reflecting the average bone/blood concentration ratio at steady-state. The model predicted median ratio of vancomycin area under the curve (AUC) for bone/AUC for serum was 44%. Observed vancomycin concentrations in bone were overall consistent with perfusion-limited distribution from blood to bone. An mPBPK model overall well described vancomycin concentrations in serum and bone.
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