title: Optimised protocol design for the screening of analgesic compounds in neuropathic pain.
abstract: 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.
authors.affiliation: Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Taneja
authors.forename: J
authors.initials: J
authors.lastname: Nyberg
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: O
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000588:Amines / Q000493:pharmacokinetics / Q000494:pharmacology; D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D015331:Cohort Studies; D003509:Cyclohexanecarboxylic Acids / Q000493:pharmacokinetics / Q000494:pharmacology; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D000077206:Gabapentin; D016015:Logistic Models; D008954:Models, Biological; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D000069583:Pregabalin; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin