Predicted metabolic drug clearance with increasing adult age

• Published in: British journal of clinical pharmacology Vol. 75; no. 4; pp. 1019 - 1028
• Main Authors: Polasek, Thomas M., Patel, Farhaan, Jensen, Berit P., Sorich, Michael J., Wiese, Michael D., Doogue, Matthew P.
• Format: Journal Article
• Language: English
• Published: England Blackwell Science Inc 01.04.2013
• Subjects: Adult; Aged; Aged, 80 and over; ageing; Aging - metabolism; Caffeine - pharmacokinetics; clearance; Computer Simulation; Desipramine - pharmacokinetics; Female; Humans; in vitro‐in vivo extrapolation; Male; Mephenytoin - pharmacokinetics; Metabolic Clearance Rate; Midazolam - pharmacokinetics; Middle Aged; modelling and simulation; Models, Biological; Pharmacokinetics; physiologically‐based pharmacokinetics; Simcyp; Warfarin - pharmacokinetics
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/j.1365-2125.2012.04446.x

Aim To determine the effect of increasing adult age on predicted metabolic drug clearance. Method 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. Results 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. Conclusion 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.