British Journal of Clinical Pharmacology 2013-04-01

Predicted metabolic drug clearance with increasing adult age.

Thomas M Polasek, Farhaan Patel, Berit P Jensen, Michael J Sorich, Michael D Wiese, Matthew P Doogue

Index: Br. J. Clin. Pharmacol. 75(4) , 1019-28, (2013)

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Abstract

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.© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.