ISBN 9783843940559

978-3-8439-4055-9, Reihe Klinische Pharmazie

Jan-Frederik Schlender
Development and Evaluation of a Physiologically Based Pharmacokinetic (PBPK) Population Model for Elderly Individuals

157 Seiten, Dissertation Rheinische Friedrich-Wilhelms-Universität Bonn (2019), Softcover, A5

Zusammenfassung / Abstract

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.

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.

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.