Sridharan Kannan, Al Daylami Amal, Ajjawi Reema, Al-Ajooz Husain, Veeramuthu Sindhan
Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
Department of Pediatrics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
Eur J Drug Metab Pharmacokinet. 2019 Dec;44(6):807-816. doi: 10.1007/s13318-019-00568-6.
Critically ill children exhibit altered pharmacokinetic parameters of vancomycin, mainly due to altered renal excretion and volume of distribution (as a result of altered plasma protein concentrations). We assessed the pharmacokinetic parameters of vancomycin in this subpopulation.
Vancomycin trough concentrations in critically ill children were obtained following first dose and at steady state. Using a one-compartment model, clearance (CL), volume of distribution (Vd), elimination half-life (t), and area under the time-concentration curve for 24 h (AUC) were estimated. Subgroup analyses were carried out, with patients differentiated based on age, renal clearance, outcome, and renal dysfunction. Protein-free vancomycin concentrations were calculated using a previously reported formula.
Twenty-two samples were evaluated for first-dose and 182 for steady-state pharmacokinetics, and similar pharmacokinetic parameter values were observed at first dose and at steady state. Only 36.4% and 47.3% of the samples attained the recommended AUC (mg·hr/L) of > 400 at first dose and at steady state, while 62.5% of the patients with renal dysfunction achieved this target. Nearly 40% of the patients had augmented renal clearance (ARC), which was associated with higher CL, shorter t, and lower AUC values. Amongst the patients with ARC, none had AUC (mg·hr/L) > 400 at first dose, while 16% achieved this target at steady state. Volume of distribution was significantly higher in infants and a decreasing trend was observed in toddlers, children, and older children at steady state. Children with renal dysfunction had lower CL, prolonged t, and higher AUC values than patients with normal renal clearance at first dose. A good correlation was observed between trough concentration and AUC, as corroborated by the area under the receiver operating characteristic curve. The median fraction of protein-free vancomycin was around 77%.
Vancomycin dosing strategies in younger children should be revisited, and increased doses should be considered for critically ill children with ARC in order to achieve therapeutic concentrations of AUC.
危重症儿童万古霉素的药代动力学参数发生改变，主要是由于肾脏排泄和分布容积改变（血浆蛋白浓度改变所致）。我们评估了该亚组人群中万古霉素的药代动力学参数。
获取危重症儿童首次给药后及稳态时的万古霉素谷浓度。采用单室模型，估算清除率（CL）、分布容积（Vd）、消除半衰期（t）以及24小时时间-浓度曲线下面积（AUC）。进行亚组分析，根据年龄、肾脏清除率、预后和肾功能不全对患者进行区分。使用先前报道的公式计算游离万古霉素浓度。
对22份首次给药样本和182份稳态药代动力学样本进行了评估，首次给药和稳态时观察到相似的药代动力学参数值。仅36.4%和47.3%的样本在首次给药和稳态时达到推荐的AUC（mg·hr/L）>400，而62.5%的肾功能不全患者达到该目标。近40%的患者有肾脏清除率增加（ARC），这与较高的CL、较短的t和较低的AUC值相关。在ARC患者中，首次给药时无一人AUC（mg·hr/L）>400，而稳态时有16%达到该目标。稳态时婴儿的分布容积显著更高，在幼儿、儿童和大龄儿童中观察到下降趋势。首次给药时，肾功能不全儿童的CL较低、t延长且AUC值高于肾脏清除率正常的患者。谷浓度与AUC之间观察到良好的相关性，接受者操作特征曲线下面积证实了这一点。游离万古霉素的中位数比例约为77%。
应重新审视年幼儿童的万古霉素给药策略，对于患有ARC的危重症儿童应考虑增加剂量，以达到AUC的治疗浓度。
