Jung Woo Jin, Park Jung-Hyuck, Goo Sungwoo, Chae Jung-Woo, Kim JaeWoo, Shin Sooyoung, Yun Hwi-Yeol
College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea; Department of New Drug Development, NEXEL Corporation, Seoul, Republic of Korea.
Clin Ther. 2021 Jan;43(1):185-194.e16. doi: 10.1016/j.clinthera.2020.10.016. Epub 2020 Dec 23.
This study aimed to determine the appropriate vancomycin dosage, considering patient size and organ maturation, by simulating the bacterial count and biomarker level for drug administration in pediatric patients with gram-positive bacterial (GPB) infections.
Natural language processing for n-gram analysis was used to detect appropriate pharmacodynamic (PD) markers in infectious disease patients. In addition, a mechanism-based model was established to describe the systemic exposure and evaluate the PD marker simultaneously in pediatric patients. A simulation study was then conducted by using a mechanism-based model to evaluate the optimal dose of vancomycin in pediatric patients.
C-reactive protein (CRP) was selected as a PD marker from an analysis of ~270,000 abstracts in PubMed. In addition, clinical results, including the vancomycin plasma concentrations and CRP levels of pediatric patients (n = 93), were collected from electronic medical records. The vancomycin pharmacokinetic model with allometric scaling and a maturation function was built as a one-compartment model, with an additional compartment for bacteria. Both the effects of vancomycin plasma concentrations on the destruction of bacteria and those of bacteria on CRP production rates were represented by using a maximum achievable effect model (E model). Simulation for dose optimization was conducted not only by using the final model but also by exploring the possibility of therapeutic failure based on the MICs of vancomycin for GPB. Clinical cure was defined as when the CRP level fell below the upper limit of the normal range. Our dose optimization simulations suggested a vancomycin dosage of 10 mg/kg every 8 h as the optimal maintenance dose for pediatric patients with a postconceptual age <30 weeks and 10 mg/kg every 6 h for older children, aged up to 12 years. In addition, the MIC of 3 μg/mL was assessed as the upper concentration limit associated with successful vancomycin treatment of GPB infections.
This study confirmed that the changes in bacterial counts and CRP levels were well described with mechanistic exposure-response modeling of vancomycin. This model can be used to determine optimal empiric doses of vancomycin and to improve therapeutic outcomes in pediatric patients with GPB.
本研究旨在通过模拟革兰氏阳性菌（GPB）感染的儿科患者给药时的细菌计数和生物标志物水平，考虑患者体型和器官成熟度，确定合适的万古霉素剂量。
采用用于n元语法分析的自然语言处理来检测传染病患者中合适的药效学（PD）标志物。此外，建立了一个基于机制的模型来描述全身暴露并同时评估儿科患者的PD标志物。然后使用基于机制的模型进行模拟研究，以评估儿科患者万古霉素的最佳剂量。
通过对PubMed中约270,000篇摘要的分析，选择C反应蛋白（CRP）作为PD标志物。此外，从电子病历中收集了包括儿科患者（n = 93）的万古霉素血浆浓度和CRP水平在内的临床结果。将具有异速生长缩放和成熟功能的万古霉素药代动力学模型构建为单室模型，并增加一个细菌室。使用最大可达到效应模型（E模型）来表示万古霉素血浆浓度对细菌破坏的影响以及细菌对CRP产生速率的影响。不仅使用最终模型进行剂量优化模拟，还基于万古霉素对GPB的最低抑菌浓度（MIC）探索治疗失败的可能性。临床治愈定义为CRP水平降至正常范围上限以下。我们的剂量优化模拟表明，对于孕龄小于30周的儿科患者，最佳维持剂量为每8小时10 mg/kg，对于年龄较大的儿童（直至12岁），最佳维持剂量为每6小时10 mg/kg。此外，3 μg/mL的MIC被评估为与万古霉素成功治疗GPB感染相关的浓度上限。
本研究证实，通过万古霉素的机制性暴露-反应模型可以很好地描述细菌计数和CRP水平的变化。该模型可用于确定万古霉素的最佳经验性剂量，并改善GPB感染儿科患者的治疗效果。
