Schlender, Jan-Frederik: Development and Evaluation of a Physiologically Based Pharmacokinetic (PBPK) Population Model for Elderly Individuals. - Bonn, 2019. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
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author = {{Jan-Frederik Schlender}},
title = {Development and Evaluation of a Physiologically Based Pharmacokinetic (PBPK) Population Model for Elderly Individuals},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2019,
month = jul,

note = {Clinical drug development is traditionally focused on young and middle-aged adults. The elderly are often underrepresented in clinical trials, even though persons aged 65 years and older receive the majority of drug prescriptions. Consequently, there is a knowledge gap on dose-exposure relationships in elderly subjects. This thesis aimed at contributing to a better understanding of the age-related mechanisms governing the pharmacokinetics (PK) in this clinically understudied population.
First, a physiologically based pharmacokinetic (PBPK) database for the course of healthy ageing was successfully established. For parameterization of the PBPK model for healthy ageing individuals, anthropometric and physiological data were identified in the literature, which were incorporated into the PBPK software PK-Sim®. Although age-related changes occurring from 65 to 100 years of age were the main focus of this work, data on anatomical and physiological changes beginning from early adulthood to the elderly age range were also included for a sound and continuous description of ageing humans. In total, 118 studies comprising 47029 male and 67419 female subjects were included to build the elderly PBPK database.
As next step, the capability of the elderly PBPK approach to predict the distribution and elimination of drugs was verified using the test compounds morphine and furosemide administered intravenously. Both drugs are cleared by a single elimination pathway. PK parameters for the two compounds in younger adults and elderly individuals were obtained from the literature. Matching virtual populations – with regard to age, gender, anthropometric measures and dosage – were generated. Profiles of plasma drug concentration over time, volume of distribution at steady-state (Vss) and elimination half-lives (t1/2) from the literature were compared to those predicted by PBPK simulations, for both younger adults and the elderly. Based on age-informed physiology, the predicted PK profiles described age-associated trends well. The root mean squared prediction error (RMSE) for the prediction of plasma concentrations for furosemide and morphine in the elderly was improved by 32% and 49%, respectively, compared to predictions without age-informed physiology. The majority of the individual Vss and t1/2 values of the two model compounds furosemide and morphine were well predicted in the elderly population, except for long furosemide half-lives.
Finally, the reliability of predictions outside the tested adult age range towards the extremes of ages was assessed using the multi-elimination pathway compound ciprofloxacin as probe drug. Mean data of 69 published clinical trials were identified and used for model building, simulation as well as the verification process. The predictive performance on both ends of the age scale was assessed using individual data of 236 pediatric and 22 geriatric patients observed in clinical trials. Ciprofloxacin model verification demonstrated no concentration-related bias and accurate predictions for the adult age range with only 4.8 % of the mean observed concentrations following intravenous and 12.1 % following oral administration outside the simulated 2-fold range. Predictions towards both extremes of ages for the area under the plasma concentration–time curve (AUC) and the maximum plasma concentration (Cmax) were reliable.
The results of this thesis support the feasibility of using a knowledge-driven PBPK ageing model to predict PK alterations throughout the entire course of ageing, and thus to optimize drug therapy also in older adult individuals. Overall, the predictive power of a thoroughly informed middle-out approach towards older adults to potentially support the decision making process for pharmacotherapy in the elderly was demonstrated. These results indicate that medication safety in geriatric patients may be greatly facilitated by the information gained from PBPK predictions.},

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