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Keywords:

  • ageing;
  • clearance;
  • in vitro-in vivo extrapolation;
  • modelling and simulation;
  • physiologically-based pharmacokinetics;
  • Simcyp®

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.