Jan-Frederik Schlender (1,2) Niklas Werner (2) Michaela Meyer (2) Kirstin Thelen (2) Thomas Eissing (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: Recently a novel whole-body physiologically-based pharmacokinetic (PBPK) ageing approach has demonstrated its feasibility to predict the pharmacokinetic disposition of exclusively glomerular filtered drugs in elderly individuals [1]. The aim of this study was to evaluate the influence of age on active processes such as tubular secretion (TS) by applying a lifespan PBPK model for digoxin.
Methods: Age-related parameters deemed necessary for an evaluation of the renal ageing process were identified in a literature search and incorporated into the PBPK modelling software PK-Sim® (Bayer Technology Services GmbH, Leverkusen, Germany) [2]. Digoxin was chosen as test compound as it is mainly cleared renally with a considerable extent of tubular secretion. A digoxin PBPK model was established for young adults based on different pre-clinical and clinical data, validated on additional data sets, and subsequently scaled to different elderly ages in order to quantify the extent of age-dependent changes of tubular secretion.
Results: The digoxin PBPK model established for young healthy adults described plasma concentration and urinary excretion data of the compound well after intravenous and oral administration. Using relative tissue expression profiles of P-glycoprotein (P-gp) derived from mRNA data [3] the contribution of P-gp to absorption, disposition and excretion was specified. The established PBPK model was used to assess age-related changes of digoxin clearance and thus quantify the percentage related to active elimination processes.
Conclusions: The knowledge-driven PBPK lifespan model offers the unique opportunity to evaluate and specify age-dependency of active processes that are difficult to measure in a clinical setting. Such a model represents a valuable tool for analysing the varying influence of multiple kinetic mechanisms with advancing age and, thus, serves to predict the pharmacokinetics of drugs in elderly.
References:
[1] Schlender JF et al., Development of a whole-body PBPK approach to assess the pharmacokinetics of xenobiotics in elderly individuals. PAGE 23, Abstr 3198,2014.
[2] Willmann S et al., PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model. Biosilico 2003; 1: 121-4.[3] Nishimura M and Naito S, Tissue-specific mRNA expression profiles of human ATPbinding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet 2005; 20: 452-77.
Reference: PAGE 24 (2015) Abstr 3611 [www.page-meeting.org/?abstract=3611]
Poster: Drug/Disease modeling - Absorption & PBPK