Document Detail

Optimised protocol design for the screening of analgesic compounds in neuropathic pain.
MedLine Citation:
PMID:  23197246     Owner:  NLM     Status:  MEDLINE    
We have previously shown how screening experiments for neuropathic pain can be optimised taking into account parameter and model uncertainty. Here we demonstrate how optimised protocols can be used to screen and rank candidate molecules. The concept is illustrated by pregabalin as a new chemical entity and gabapentin as a reference compound. ED-optimality was applied to a logistic regression model describing the relationship between drug exposure and response to evoked pain in the complete Freund's adjuvant (CFA) model in rats. Design variables for optimisation of the experimental protocol included dose levels and sampling times. Prior information from the reference compound was used in conjunction with relative in vitro potency as priors. Results from simulated scenarios were then combined with fitting of experimental data to estimate precision and bias of model parameters for the empirical and optimised designs. The pharmacokinetics of pregabalin was described by a two-compartment model. The expected value of EC(50) of pregabalin was 637.5 ng ml(-1). Model-based analysis of the data yielded median (range) of EC(50) values of 1,125 (898-2412) ng ml(-1) for the empirical protocol and 755 (189-756) ng ml(-1) for the optimised design. In contrast to current practice, optimal design entails different sampling schedule across dose levels. ED-optimised designs should become standard practice in the screening of candidate molecules. It ensures lower bias when estimating the drug potency, facilitating accurate ranking and selection of compounds for further development.
A Taneja; J Nyberg; M Danhof; O Della Pasqua
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Publication Detail:
Type:  Journal Article     Date:  2012-11-30
Journal Detail:
Title:  Journal of pharmacokinetics and pharmacodynamics     Volume:  39     ISSN:  1573-8744     ISO Abbreviation:  J Pharmacokinet Pharmacodyn     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-05     Completed Date:  2013-08-20     Revised Date:  2013-08-21    
Medline Journal Info:
Nlm Unique ID:  101096520     Medline TA:  J Pharmacokinet Pharmacodyn     Country:  United States    
Other Details:
Languages:  eng     Pagination:  661-71     Citation Subset:  IM    
Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.
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MeSH Terms
Amines / pharmacokinetics,  pharmacology
Analgesics / pharmacokinetics,  pharmacology*
Cohort Studies
Cyclohexanecarboxylic Acids / pharmacokinetics,  pharmacology
Double-Blind Method
Drug Evaluation, Preclinical / methods*
Logistic Models
Models, Biological*
Neuralgia / drug therapy*,  metabolism
Random Allocation
Rats, Sprague-Dawley
gamma-Aminobutyric Acid / analogs & derivatives,  pharmacokinetics,  pharmacology
Reg. No./Substance:
0/Amines; 0/Analgesics; 0/Cyclohexanecarboxylic Acids; 55JG375S6M/pregabalin; 56-12-2/gamma-Aminobutyric Acid; 6CW7F3G59X/gabapentin

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