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Erschienen in: Clinical Pharmacokinetics 8/2016

25.02.2016 | Original Research Article

Development of a Physiologically Based Pharmacokinetic/Pharmacodynamic Model to Predict the Impact of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics Represented by Receptor/Transporter Occupancy of Central Nervous System Drugs

verfasst von: Saeed Alqahtani, Amal Kaddoumi

Erschienen in: Clinical Pharmacokinetics | Ausgabe 8/2016

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Abstract

Background

Genetic polymorphisms are major determinants of individual variability in a drug’s efficacy and safety, which is one of the main challenges in current clinical practice and drug development. The aim of this work was to develop a physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model to predict changes in the PK parameters associated with genetic polymorphisms and the impact of these changes on drugs’ PD effect.

Methods

We developed PBPK models for two central nervous system (CNS) medications, namely quetiapine and fluvoxamine that are substrates for polymorphic enzymes by incorporating the corresponding alterations in the enzyme activity and/or abundance. Then, the PBPK models were linked to PD models to predict the influence of these changes on the drugs’ PD effect.

Results

Application of the PBPK models for prediction of phenotypic differences in the PKs compared favorably with reported clinical data. In addition, the PBPK/PD models were able to describe the relationship between the drugs’ PD effect and their unbound fractions in the brain and predict changes in receptor/transporter occupancy percentages, obtained from positron emission tomography occupancy studies, associated with genetic variations.

Conclusions

This work provides a simplified approach to predict the influence of genetic polymorphisms on the PK parameters and associated PD effect for CNS drugs. The impact of these polymorphisms on the drugs’ PD requires further in vivo validation.
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Metadaten
Titel
Development of a Physiologically Based Pharmacokinetic/Pharmacodynamic Model to Predict the Impact of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics Represented by Receptor/Transporter Occupancy of Central Nervous System Drugs
verfasst von
Saeed Alqahtani
Amal Kaddoumi
Publikationsdatum
25.02.2016
Verlag
Springer International Publishing
Erschienen in
Clinical Pharmacokinetics / Ausgabe 8/2016
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-016-0367-6

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