Predicted metabolic drug clearance with increasing adult age

Aim: To determine the effect of increasing adult age on predicted metabolic drug clearance. Method: Predicted metabolic drug clearances (CL_PT) 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). CL_PT 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 CL_PT were described. Results: Predicted metabolic drug clearances decreased with increasing adult age to approximately 65-70 years: caffeine from 1.5 to 1.0mlmin^-1kg^-1 (a 33% decrease), S-warfarin from 0.100 to 0.064mlmin^-1kg^-1 (36%), S-mephenytoin from 4.1 to 2.5mlmin^-1kg^-1 (39%), desipramine from 10.6 to 7.3mlmin^-1kg^-1 (31%) and midazolam from 5.4 to 3.9mlmin^-1kg^-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 CL_PT was observed in females, but this was only statistically significant in larger virtual trials. Physiological parameters that determine CL_PT decreased with increasing adult age: mean microsomal proteing^-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.