Medellín-Garibay Susanna E, Ortiz-Martín Belén, Rueda-Naharro Aída, García Benito, Romano-Moreno Silvia, Barcia Emilia
Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza de Ramón y Cajal, Ciudad Universitaria, 28040 Madrid, Spain
Servicio de Farmacia, Hospital Universitario Severo Ochoa, Avenida de Orellana, 28911 Leganés, Spain.
J Antimicrob Chemother. 2016 Feb;71(2):471-9. doi: 10.1093/jac/dkv372. Epub 2015 Nov 14.
The objectives of this study were to characterize the population pharmacokinetics of vancomycin in trauma patients and to propose dosing schemes to optimize therapy.
Trauma patients from Hospital Universitario Severo Ochoa (Spain) receiving intravenous vancomycin and routine therapeutic drug monitoring were included. Concentrations and time data were retrospectively collected, and population modelling was performed with NONMEM 7.2; internal and external validations were performed to probe the final model. Finally, several simulations were executed to propose dosing guidelines to reach expected vancomycin concentrations.
A total of 118 trauma patients were included; the population was 45% males, with a mean age of 77 years (range 37-100 years) and a mean total body weight (TBW) of 72 kg (range 38-110 kg). The pharmacokinetics of vancomycin was best described by a two-compartment open model; creatinine clearance (CLCR) was related to vancomycin clearance (0.49 ± 0.04 L/h), being diminished by the presence of furosemide (0.34 ± 0.05 L/h). TBW influenced both the central volume of distribution (V1 = 0.74 ± 0.1 L/kg) and peripheral volume of distribution (V2 = 5.9 ± 2 L/kg), but patients with age >65 years showed a larger V1 (1.07 ± 0.1 L/kg). Bootstrapping was performed to internally validate the stability of the final model. External validation was developed using an alternate population of 40 patients with the same characteristics. The validated model was compared with population pharmacokinetic models previously published and showed better predictive performance for trauma patients than the current one. This final model allowed us to propose a new practical dose guideline to reach higher trough concentrations (15-20 mg/L) and AUC0-24/MIC ratios of more than 400 after 4 days of vancomycin treatment.
A new population model was described for trauma patients to optimize vancomycin therapy, showing precise predictive performance to be applied for therapeutic drug monitoring and providing a new practical dose guideline that considers CLCR and concomitant administration of furosemide for these patients.
本研究的目的是描述创伤患者中万古霉素的群体药代动力学，并提出优化治疗的给药方案。
纳入西班牙塞韦罗·奥乔亚大学医院接受静脉注射万古霉素及常规治疗药物监测的创伤患者。回顾性收集浓度和时间数据，并用NONMEM 7.2进行群体建模；进行内部和外部验证以检验最终模型。最后，进行了几次模拟以提出达到预期万古霉素浓度的给药指南。
共纳入118例创伤患者；该群体中男性占45%，平均年龄77岁（范围37 - 100岁），平均总体重（TBW）72 kg（范围38 - 110 kg）。万古霉素的药代动力学最佳用二室开放模型描述；肌酐清除率（CLCR）与万古霉素清除率相关（0.49±0.04 L/h），使用呋塞米会使其降低（0.34±0.05 L/h）。TBW影响中央分布容积（V1 = 0.74±0.1 L/kg）和外周分布容积（V2 = 5.9±2 L/kg），但年龄>65岁的患者V1更大（1.07±0.1 L/kg）。进行自举法以内部验证最终模型的稳定性。使用40例具有相同特征的替代患者群体进行外部验证。将验证后的模型与先前发表的群体药代动力学模型进行比较，结果显示其对创伤患者的预测性能优于当前模型。该最终模型使我们能够提出一项新的实用剂量指南，以在万古霉素治疗4天后达到更高的谷浓度（15 - 20 mg/L）以及AUC0 - 24/MIC比值大于400。
描述了一种针对创伤患者的新群体模型以优化万古霉素治疗，显示出精确的预测性能，可应用于治疗药物监测，并为这些患者提供了一种考虑CLCR和呋塞米联合使用情况的新实用剂量指南。
