Wang Peile, Zhang Qiwen, Feng Min, Sun Tongwen, Yang Jing, Zhang Xiaojian
Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China.
Front Pharmacol. 2021 Nov 22;12:754844. doi: 10.3389/fphar.2021.754844. eCollection 2021.
Polymyxin B is an effective but potentially nephrotoxic antibiotic that is commonly used to treat resistant Gram-negative infections. As a weight-based dosing drug, obese patients may be at a high risk of nephrotoxicity. However, the pharmacokinetics and dosing recommendations for this population are currently lacking. This study aimed to describe the polymyxin B population pharmacokinetics and to evaluate pharmacokinetic/pharmacodynamics (PK/PD) target attainment for obese patients. This study included 26 patients (body mass index, BMI >30) who received polymyxin B for ≥3 days. The total body weight (TBW) ranged from 75 to 125 kg, and the BMI ranged from 30.04 to 40.35. A two-compartment model adequately described the data using Phoenix NLME software. Monte Carlo simulation was used to assess polymyxin B exposure and the probability of target attainment (PTA). As a result, body weight had no significant effect on polymyxin B pharmacokinetics. According to model-based simulation, adjusted body weight (ABW)-based regimens had a high probability of achieving optimal exposure with minimal toxicity risk by comparing TBW and ideal body weight (IBW)-based regimens. The fixed dose of 125 mg or 150 mg q12h had a high toxicity risk. PTA results showed that TBW, IBW, and ABW-based regimens had similar PTA values. Therefore, for obese patients, ABW-based regimens but with a daily dose <250 mg have a high likelihood of achieving an AUC of 50-100 mg h/L and attaining PK/PD targets with the MIC ≤0.5 mg/L.
多粘菌素B是一种有效的但具有潜在肾毒性的抗生素，常用于治疗耐药革兰氏阴性菌感染。作为一种基于体重给药的药物，肥胖患者可能有较高的肾毒性风险。然而，目前缺乏该人群的药代动力学和给药建议。本研究旨在描述多粘菌素B的群体药代动力学，并评估肥胖患者的药代动力学/药效学（PK/PD）目标达成情况。本研究纳入了26例（体重指数，BMI>30）接受多粘菌素B治疗≥3天的患者。总体重（TBW）范围为75至125 kg，BMI范围为30.04至40.35。使用Phoenix NLME软件，一个二室模型充分描述了数据。采用蒙特卡洛模拟评估多粘菌素B的暴露情况和目标达成概率（PTA）。结果，体重对多粘菌素B的药代动力学没有显著影响。根据基于模型的模拟，与基于TBW和理想体重（IBW）的给药方案相比，基于调整体重（ABW）的给药方案有很高的概率实现最佳暴露且毒性风险最小。125 mg或150 mg q12h的固定剂量有很高的毒性风险。PTA结果显示，基于TBW、IBW和ABW的给药方案具有相似的PTA值。因此，对于肥胖患者，基于ABW的给药方案但每日剂量<250 mg有很高的可能性实现50 - 100 mg·h/L的AUC，并在MIC≤0.5 mg/L时达成PK/PD目标。
