Exploratory Translational Modeling Approach in Drug Development to Predict Human Brain Pharmacokinetics and Pharmacologically Relevant Clinical Doses

The central nervous system (CNS) pharmacokinetics (PK) of drugs that have pharmacological targets in the brain are not often understood during drug development, and this gap in knowledge is a limitation in providing a quantitative framework for translating nonclinical pharmacologic data to the clini...

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Bibliographic Details
Published in:Drug metabolism and disposition 2012-05, Vol.40 (5), p.877-883
Main Authors: Kielbasa, W., Stratford, R.E.
Format: Article
Language:English
Subjects:
Animals
Atomoxetine Hydrochloride
Biomarkers - metabolism
Brain - metabolism
Clinical Medicine
Dose-Response Relationship, Drug
Drug Discovery - methods
Drug Evaluation, Preclinical
Duloxetine Hydrochloride
Extracellular Fluid - metabolism
Humans
Male
Microdialysis
Models, Biological
Predictive Value of Tests
Propylamines - administration & dosage
Propylamines - pharmacokinetics
Rats
Rats, Sprague-Dawley
Species Specificity
Thiophenes - administration & dosage
Thiophenes - pharmacokinetics
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Summary:The central nervous system (CNS) pharmacokinetics (PK) of drugs that have pharmacological targets in the brain are not often understood during drug development, and this gap in knowledge is a limitation in providing a quantitative framework for translating nonclinical pharmacologic data to the clinical patient population. A focus of translational sciences is to improve the efficiency of clinical trial design via a more judicious selection of clinical doses on the basis of nonclinical data. We hypothesize that this can be achieved for CNS-acting drugs based on knowledge of CNS PK and brain target engagement obtained in nonclinical studies. Translating CNS PK models from rat to human can allow for the prediction of human brain PK and the human dose-brain exposure relationship, which can provide insight on the clinical dose(s) having potential brain activity and target engagement. In this study, we explored the potential utility of this translational approach using rat brain microdialysis and PK modeling techniques to predict human brain extracellular fluid PK of atomoxetine and duloxetine. The results show that this translational approach merits consideration as a means to support the clinical development of CNS-mediated drug candidates by enhancing the ability to predict pharmacologically relevant doses in humans in the absence of or in association with other biomarker approaches.
ISSN:0090-9556
1521-009X
DOI:10.1124/dmd.111.043554