Johnston Claire, Hilmer Sarah N, McLachlan Andrew J, Matthews Slade T, Carroll Peter R, Kirkpatrick Carl M
Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Eur J Clin Pharmacol. 2014 May;70(5):549-55. doi: 10.1007/s00228-014-1652-7. Epub 2014 Feb 14.
Frailty, a multifactorial biological syndrome characterized by a cumulative dysregulation of physiological processes, is associated with changes in pharmacokinetics and pharmacodynamics. The aim of this study was to quantify the effect of frailty on glomerular filtration of drugs, using the probe drug gentamicin.
Gentamicin concentrations and clinical data including the Reported Edmonton Frail Scale score were pooled from two prospective observational inpatient studies, one on prophylactic gentamicin for urologic surgery and one on therapeutic gentamicin for the empiric treatment of sepsis. Population pharmacokinetic modeling was performed using non-linear mixed effects modeling (NONMEM program) to determine the impact of frailty on gentamicin clearance.
A one-compartment linear pharmacokinetic model best described the data and the addition of frailty to the model reduced the random variability in gentamicin clearance by 12 % after adjustment for renal function (estimated creatinine clearance using lean body weight) and lean body weight. Frail patients had an approximately 12 % lower (bootstrapping results: 14 % median) gentamicin clearance than non-frail patients (calculated as a fractional effect of frailty).
Frailty may independently predict reduced clearance of gentamicin in older patients. Frailty could be considered in the development of dosing guidelines for drugs that undergo significant excretion through glomerular filtration.
衰弱是一种以生理过程累积失调为特征的多因素生物综合征，与药代动力学和药效学的变化有关。本研究的目的是使用探针药物庆大霉素来量化衰弱对药物肾小球滤过的影响。
从两项前瞻性观察性住院患者研究中汇总庆大霉素浓度和临床数据，包括埃德蒙顿衰弱量表报告得分，一项研究是关于泌尿外科手术预防性使用庆大霉素，另一项研究是关于经验性治疗脓毒症的治疗性使用庆大霉素。使用非线性混合效应模型（NONMEM程序）进行群体药代动力学建模，以确定衰弱对庆大霉素清除率的影响。
单室线性药代动力学模型最能描述数据，在调整肾功能（使用瘦体重估计肌酐清除率）和瘦体重后，将衰弱因素添加到模型中可使庆大霉素清除率的随机变异性降低12%。衰弱患者的庆大霉素清除率比非衰弱患者低约12%（自举结果：中位数为14%）（计算为衰弱的分数效应）。
衰弱可能独立预测老年患者庆大霉素清除率降低。在制定通过肾小球滤过进行大量排泄的药物给药指南时，应考虑衰弱因素。
