Department of Clinical Pharmacology, Flinders University and Flinders Medical Centre, Adelaide, SA, Australia.
Br J Clin Pharmacol. 2013 Apr;75(4):1019-28. doi: 10.1111/j.1365-2125.2012.04446.x.
To determine the effect of increasing adult age on predicted metabolic drug clearance.
Predicted metabolic drug clearances (CLPT ) were determined using in vitro-in vivo extrapolation coupled with physiological-based pharmacokinetic modelling and simulation (IVIVE-PBPK) in Simcyp®. Simulations were conducted using CYP-selective 'probe' drugs with subjects in 5 year age groups (20-25 to 90-95 years). CLPT values were compared with human pharmacokinetic data stratified according to age (young = 20-40 years and elderly = 65-85 years) and gender. Age-related changes in the physiological parameters used for IVIVE of CLPT were described.
Predicted metabolic drug clearances decreased with increasing adult age to approximately 65-70 years: caffeine from 1.5 to 1.0 ml min(-1) kg(-1) (a 33% decrease), S-warfarin from 0.100 to 0.064 ml min(-1) kg(-1) (36%), S-mephenytoin from 4.1 to 2.5 ml min(-1) kg(-1) (39%), desipramine from 10.6 to 7.3 ml min(-1) kg(-1) (31%) and midazolam from 5.4 to 3.9 ml min(-1) kg(-1) (27%). Except for S-mephenytoin, predictions were within 3.5-fold of clearances from clinical studies when stratified by age and gender. A trend towards higher CLPT was observed in females, but this was only statistically significant in larger virtual trials. Physiological parameters that determine CLPT decreased with increasing adult age: mean microsomal protein g(-1) of liver, liver weight, hepatic blood flow and human serum albumin concentration.
Decreased metabolic clearance in the elderly was predicted by Simcyp® and was generally consistent with limited clinical data for four out of five drugs studied and the broader literature for drugs metabolized by CYP enzymes. IVIVE-PBPK may be increasingly useful in predicting metabolic drug clearance in the elderly.
确定成年年龄增加对预测代谢药物清除率的影响。
使用体外-体内外推法结合基于生理的药代动力学模型和模拟（IVIVE-PBPK）在 Simcyp®中确定预测代谢药物清除率（CLPT）。使用 CYP 选择性“探针”药物在 5 岁年龄组（20-25 至 90-95 岁）中进行模拟。将 CLPT 值与根据年龄（年轻=20-40 岁和老年=65-85 岁）和性别分层的人体药代动力学数据进行比较。描述了用于 CLPT IVIVE 的生理参数随年龄的变化。
预测代谢药物清除率随成年年龄的增加而降低，至约 65-70 岁：咖啡因从 1.5 降至 1.0 ml·min-1·kg-1（下降 33%），S-华法林从 0.100 降至 0.064 ml·min-1·kg-1（36%），S-美芬妥英从 4.1 降至 2.5 ml·min-1·kg-1（39%），去甲替林从 10.6 降至 7.3 ml·min-1·kg-1（31%），咪达唑仑从 5.4 降至 3.9 ml·min-1·kg-1（27%）。除 S-美芬妥英外，按年龄和性别分层的临床研究清除率的预测值在 3.5 倍以内。在女性中观察到 CLPT 升高的趋势，但在较大的虚拟试验中仅具有统计学意义。决定 CLPT 的生理参数随成年年龄的增加而降低：肝微粒体蛋白 g-1、肝重量、肝血流量和人血清白蛋白浓度。
Simcyp®预测老年人代谢清除率降低，对于研究的五种药物中的四种药物，以及更广泛的 CYP 酶代谢药物的文献，与有限的临床数据总体一致。IVIVE-PBPK 可能在预测老年人代谢药物清除率方面变得越来越有用。
