Manoranjenni Chetty, Felix Stader
Simcyp (A Certara Company), Level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ.
Objectives: Antidepressants, anxiolytics and statins are commonly prescribed in elderly patients. This group of patients are generally not included in clinical trials that investigate the relevant doses of these drugs. Drug dose regimens used in the older patients are frequently determined by trial and error or extrapolated from doses relevant to young adults. Physiological changes that may potentially impact drug exposure in the elderly are frequently reported, although they may be challenging to quantify. Physiologically based pharmacokinetic (PBPK) modelling offers the opportunity to explore and predict such changes in large virtual patient populations. The Simcyp population-based PBPK Geriatrics model accounts for age-related physiological changes such as demographic distribution, intestinal transit time, liver volume, kidney weight, renal function and some metabolic enzymes. This model does not account for frailty. The objective of this study was to predict potential differences in drug exposure between elderly and young patients, using the geriatrics and healthy volunteer models within the Simcyp simulator.
Methods: Two drugs from each of the above drug classes were selected from the Simcyp library for this analysis. They included fluoxetine, desipramine, midazolam, triazolam, pravastatin and rosuvastatin. Using the compound files within the simulator, simulations were run using 10 trials of 100 subjects each, where 500 of the subjects were young healthy Caucasians aged between 18 and 46 years, while the other 500 subjects were geriatric Caucasians aged between 66 and 80 years. Drug exposures, as assessed by area under the plasma concentration versus time curve (AUC0-t) and maximum plasma concentration (Cmax) or clearance (CL) of 40 mg fluoxetine, 50 mg desipramine, 0.03mg/kg midazolam, 0.25 mg triazolam, 20 mg pravastatin and 40 mg rosuvastatin were simulated and compared with observed values. The ratio of the predicted and observed drug exposure in both young and elderly subjects were first evaluated to verify the performance of the PBPK models. Drug exposures in elderly subjects were then compared with that in young subjects.
Results: Comparison of the predicted drug exposure in both young and elderly with the corresponding observed values indicated that the PBPK models performed acceptably for the six drugs. Predicted versus observed ratios for the comparative % decrease in exposure between young and elderly for the drugs were: desipramine 1.20; fluoxetine 1.3; midazolam 0.96; triazolam 1.26; rosuvastatin 0.75 and pravastatin 0.93. Apart from fluoxetine, where no significant change was predicted between the young and elderly, increased exposure to the other drugs was predicted in elderly subjects.
Conclusions: Acceptable predictions of the changes in the exposure of the selected drugs in elderly subjects were obtained in this study, suggesting that this approach could be a useful tool for dosage predictions in elderly subjects. Further verification of the model with a larger number of compounds is warranted.
Reference: PAGE 27 (2018) Abstr 8618 [www.page-meeting.org/?abstract=8618]
Poster: Drug/Disease Modelling - Absorption & PBPK