Predicted metabolic drug clearance with increasing adult age
Article first published online: 15 MAR 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 4, pages 1019–1028, April 2013
How to Cite
Polasek, T. M., Patel, F., Jensen, B. P., Sorich, M. J., Wiese, M. D. and Doogue, M. P. (2013), Predicted metabolic drug clearance with increasing adult age. British Journal of Clinical Pharmacology, 75: 1019–1028. doi: 10.1111/j.1365-2125.2012.04446.x
- Issue published online: 15 MAR 2013
- Article first published online: 15 MAR 2013
- Accepted manuscript online: 24 AUG 2012 04:10AM EST
- Manuscript Accepted: 16 AUG 2012
- Manuscript Received: 14 MAR 2012
- in vitro-in vivo extrapolation;
- modelling and simulation;
- physiologically-based pharmacokinetics;
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.