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PK/PD assessment in CNS drug discovery: Prediction of CSF concentration in rodents for P-glycoprotein substrates and application to in vivo potency estimation.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2013 Jun 01; Vol. 85 (11), pp. 1684-99. Date of Electronic Publication: 2013 Feb 27. - Publication Year :
- 2013
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Abstract
- The unbound drug concentration in brain parenchyma is considered to be the relevant driver for interaction with central nervous system (CNS) biological targets. Drug levels in cerebrospinal fluid (C&#95;CSF) are frequently used surrogates for the unbound concentrations in brain. For drugs actively transported across the blood-brain barrier (BBB), C&#95;CSF differs from unbound plasma concentration (Cu&#95;p) to an extent that is commonly unknown. In this study, the relationship between CSF-to-unbound plasma drug partitioning in rats and the mouse Pgp (Mdr1a) efflux ratio (ER) obtained from in vitro transcellular studies has been investigated for a set of 61 CNS compounds exhibiting substantial diversity in chemical structure and physico-chemical properties. In order to understand the in vitro-in vivo extrapolation of Pgp efflux, a mechanistic model was derived relating in vivo CNS distribution kinetics to in vitro active transport. The model was applied to predict C&#95;CSF from Cu&#95;p and ER data for 19 proprietary Roche CNS drug candidates. The calculated CSF concentrations were correlated with CNS pharmacodynamic responses observed in rodent models. The correlation between in vitro and in vivo potency for different pharmacological endpoints indicated that the predicted C&#95;CSF is a valuable surrogate of the concentration at the target site. Overall, C&#95;CSF proved superior description of PK/PD data than unbound plasma or total brain concentration for Mdr1a substrates. Predicted C&#95;CSF can be used as a default approach to understand the PK/PD relationships in CNS efficacy models and can support the extrapolation of efficacious brain exposure for new drug candidates from rodent to man.<br /> (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Blood Proteins metabolism
Central Nervous System Agents cerebrospinal fluid
Cluster Analysis
LLC-PK1 Cells
Mice
Models, Theoretical
Rats
Swine
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Central Nervous System Agents pharmacokinetics
Central Nervous System Agents pharmacology
Drug Discovery
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 85
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23454189
- Full Text :
- https://doi.org/10.1016/j.bcp.2013.02.021