Department of Pharmacy, Gongli Hospital of Pudong New Area in Shanghai, Shanghai, China; Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Tongji University, Shanghai, China.
Int J Antimicrob Agents. 2016 Mar;47(3):202-9. doi: 10.1016/j.ijantimicag.2015.12.018. Epub 2016 Jan 30.
In this study, a population pharmacokinetic (PPK) model of biapenem in Chinese patients with lower respiratory tract infections (LRTIs) was developed and optimal dosage regimens based on Monte Carlo simulation were proposed. A total of 297 plasma samples from 124 Chinese patients were assayed chromatographically in a prospective, single-centre, open-label study, and pharmacokinetic parameters were analysed using NONMEN. Creatinine clearance (CLCr) was found to be the most significant covariate affecting drug clearance. The final PPK model was: CL (L/h)=9.89+(CLCr-66.56)×0.049; Vc (L)=13; Q (L/h)=8.74; and Vp (L)=4.09. Monte Carlo simulation indicated that for a target of ≥40% T>MIC (duration that the plasma level exceeds the causative pathogen's MIC), the biapenem pharmacokinetic/pharmacodynamic (PK/PD) breakpoint was 4μg/mL for doses of 0.3g every 6h (3-h infusion) and 1.2g (24-h continuous infusion). For a target of ≥80% T>MIC, the PK/PD breakpoint was 4μg/mL for a dose of 1.2g (24-h continuous infusion). The probability of target attainment (PTA) could not achieve ≥90% at the usual biapenem dosage regimen (0.3g every 12h, 0.5-h infusion) when the MIC of the pathogenic bacteria was 4μg/mL, which most likely resulted in unsatisfactory clinical outcomes in Chinese patients with LRTIs. Higher doses and longer infusion time would be appropriate for empirical therapy. When the patient's symptoms indicated a strong suspicion of Pseudomonas aeruginosa or Acinetobacter baumannii infection, it may be more appropriate for combination therapy with other antibacterial agents.
在这项研究中，开发了一种比阿培南在中国下呼吸道感染（LRTIs）患者中的群体药代动力学（PPK）模型，并基于蒙特卡罗模拟提出了最佳剂量方案。在一项前瞻性、单中心、开放标签的研究中，共分析了 124 名中国患者的 297 份血浆样本，使用 NONMEN 分析药代动力学参数。发现肌酐清除率（CLCr）是影响药物清除率的最重要的协变量。最终的 PPK 模型为：CL（L/h）=9.89+（CLCr-66.56）×0.049；Vc（L）=13；Q（L/h）=8.74；和 Vp（L）=4.09。蒙特卡罗模拟表明，对于目标 T>MIC（血浆水平超过病原体 MIC 的持续时间）≥40%，比阿培南药代动力学/药效学（PK/PD）的折点为 4μg/mL，剂量为 0.3g 每 6 小时（3 小时输注）和 1.2g（24 小时连续输注）。对于目标 T>MIC≥80%，PK/PD 折点为 4μg/mL，剂量为 1.2g（24 小时连续输注）。当病原体的 MIC 为 4μg/mL 时，常用比阿培南剂量方案（0.3g 每 12 小时，0.5 小时输注）的目标达成率（PTA）不能达到≥90%，这很可能导致中国 LRTIs 患者的临床疗效不理想。更高的剂量和更长的输注时间可能适用于经验性治疗。当患者的症状强烈怀疑感染铜绿假单胞菌或鲍曼不动杆菌时，与其他抗菌药物联合治疗可能更为合适。
