Heterogeneous drug tissue binding in brain regions of rats, Alzheimer\u2019s patients and controls: impact on translational drug development

Sofia Gustafsson,Irena Loryan,Margareta Hammarlund-Udenaes,Erik Lampa,Dag Sehlin

doi:10.1038/s41598-019-41828-4

Sofia Gustafsson, Irena Loryan + Show 3 more

Open Access

https://doi.org/10.1038/s41598-019-41828-4

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Journal: Scientific Reports	Publication Date: Mar 29, 2019
Citations: 15	License type: open-access

Affiliation: Uppsala University, Science for Life Laboratory

Abstract

For preclinical and clinical assessment of therapeutically relevant unbound, free, brain concentrations, the pharmacokinetic parameter fraction of unbound drug in brain (fu,brain) is commonly used to compensate total drug concentrations for nonspecific brain tissue binding (BTB). As, homogenous BTB is assumed between species and in health and disease, rat BTB is routinely used. The impact of Alzheimer’s disease (AD) on drug BTB in brain regions of interest (ROI), i.e., fu,brain,ROI, is yet unclear. This study for the first time provides insight into regional drug BTB and the validity of employing rat fu,brain,ROI as a surrogate of human BTB, by investigating five marketed drugs in post-mortem tissue from AD patients (n = 6) and age-matched controls (n = 6). Heterogeneous drug BTB was observed in all within group comparisons independent of disease and species. The findings oppose the assumption of uniform BTB, highlighting the need of case-by-case evaluation of fu,brain,ROI in translational CNS research.

Highlights

The failure rate in CNS drug development is high and the struggle to find curative treatments for neurodegenerative disorders like Alzheimer’s disease (AD) is a costly mission for those companies undertaking it[1,2]
If Positron emission tomography (PET) is to be used in humans for the study of unbound drug concentrations and further blood-brain barrier (BBB) transport, it is essential that accurate compensation is made for drug intra-brain distribution in order to generate reliable estimates
A sensitivity analysis showed that the inclusion or exclusion of ID 6 from the control group did not have any major impact on the conclusions of the statistical analysis performed on the regional brain tissue binding (BTB) dataset

Summary

Introduction

The failure rate in CNS drug development is high and the struggle to find curative treatments for neurodegenerative disorders like Alzheimer’s disease (AD) is a costly mission for those companies undertaking it[1,2]. The regional within-group comparison of the AD donors, revealed that three out of the five studied drugs were characterized by a lower BTB in CRB compared to other brain regions, similar to the results in controls, while being more pronounced (Fig. 3, Table S2).

Results

Conclusion