Abstract
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 (R). Simulations were conducted using CYP-selective probe' drugs with subjects in 5 year age groups (2025 to 9095 years). CLPT values were compared with human pharmacokinetic data stratified according to age (young = 2040 years and elderly = 6585 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 6570 years: caffeine from 1.5 to 1.0mlmin1kg1 (a 33% decrease), S-warfarin from 0.100 to 0.064mlmin1kg1 (36%), S-mephenytoin from 4.1 to 2.5mlmin1kg1 (39%), desipramine from 10.6 to 7.3mlmin1kg1 (31%) and midazolam from 5.4 to 3.9mlmin1kg1 (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 proteing1 of liver, liver weight, hepatic blood flow and human serum albumin concentration. Conclusion Decreased metabolic clearance in the elderly was predicted by Simcyp (R) 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.