Jan-Frederik Schlender (1,2) Kirstin Thelen (2) Michaela Meyer (2) Stefan Willmann (2) and Ulrich Jaehde (1)
(1) Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Germany (2) Bayer Technology Services GmbH, Computational Systems Biology, 51368 Leverkusen, Germany
Objectives: Physiologically-based pharmacokinetic (PBPK) models have been widely used to assess drug kinetics in special populations. Although the need of PBPK models for healthy and frailed elderly populations has been stressed out several times, a knowledge-driven model has not been developed yet [1,2]. The aim of this study was to develop a whole-body PBPK approach to understand xenobiotic exposure in healthy aged Caucasian (65-100 years).
Methods: Anthropometric and physiological parameters related to ageing, and essentials for the prediction of drug disposition were gained from peer-reviewed literature. Age dependences for organ weights, blood flows, cardiac output, glomerular filtration rate, protein levels, enzyme activities, and tissue composition were validated and summarized in a database. A lifespan whole-body PBPK model was then developed and incorporated into the PK-Sim® database (Bayer Technology Services GmbH, Leverkusen, Germany). The model was subsequently scaled up to different ages and compared to literature values to verify the model over the human lifespan.
Results: 88 publications resulting in 724 data records for healthy elderly Caucasian individuals were gathered and processed to the database. The developed PBPK approach was verified and successfully described the age-related changes in physiological parameters.
Conclusions: This study validated the usage of a knowledge-driven PBPK lifespan model. With this developed model, anatomical and (patho-)physiological age-dependences can be predicted throughout the entire age-range. Ultimately, this model could be applied as a valuable tool to optimize the drug use, and would increase the efficiency of geriatric clinical trials, minimizing possible side effects due to drug-drug interactions.
References:
[1] Thompson, C.M., et al., Database for physiologically based pharmacokinetic (PBPK) modeling: physiological data for healthy and health-impaired elderly. J Toxicol Environ Health B Crit Rev. 2009 Jan;12(1):1-24.
[2] Della Casa Alberighi O., et al., Response to “Physiologically Based Pharmacokinetic Modeling at the Extremes of Age”. Clin Pharmacol Ther. 2013;93(2):149.
[3] Willmann, S., et al., PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model. Biosilico 2003 1(4): 121-4
Reference: PAGE 23 (2014) Abstr 3198 [www.page-meeting.org/?abstract=3198]
Poster: Drug/Disease modeling - Absorption & PBPK