Development of a model for robust and exploratory analysis of the rodent brief-access taste aversion data

Abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. DEVELOPMENT OF A MODEL FOR ROBUST AND EXPLORATORY ANALYSIS OF THE RODENT BRIEF-ACCESS TASTE ABSTRACTThe rodent brief-access taste aversion (BATA) model is an efficient in vivo screening tool for taste assessment. A new E max (maximum effect attributable to the drug) model was developed and further investigated in comparison to three previously published models for analysing the rodent BATA data; the robustness of all the models was discussed.The rodent BATA data were obtained from a series of experiments conducted with a bitter reference compound, quinine hydrochloride dihydrate (QHD). A new E max model that could be applied to both "lick numbers" and "lick ratios" was built and three published models that used lick ratios were employed for analysing the BATA data. IC 50 , the concentration that inhibits 50% of the maximum lick numbers, quantified the oral aversiveness of QHD. One thousand bootstrap datasets were generated from the original data. All models were applied to estimate the confidence intervals of the IC 50s without symmetric assumption.The IC 50 value obtained from the new E max model was 0.0496 mM (95% CI 0.0297-0.0857) using the lick numbers for analysis, while an IC 50 of 0.0502 mM (95% CI 0.0267-0.0859) was acquired with the lick ratios. Except from one published model, the IC 50 values have a similar range for the 95% CI.The new E max model enabled the analysis of both "lick numbers" and "lick ratios" whereas other models could only handle data presented as "lick ratios". IC 50s obtained with these two types of datasets showed similarity among all models thereby justified the robustness of the new E max model. KEY WORDSBrief-access taste aversion, lickometer, bitterness, E max model, NONMEM

Development and evaluation of an oral fast disintegrating anti-allergic film using hot-melt extrusion technology

“…The rodent brief-access taste aversion (BATA) model is one of the popular approaches used for taste evaluation [39–45]. In this model, rodents such as mice or rats, are mildly water-deprived and then put into as “lickometer” which records the number of “licks” that the rodents make to different concentrations of the compound under test samples presented in several sipper tubes [46]. Typically, a low number of licks compared to water will indicate an aversive taste [46].…”

Bitter tastant responses in the amoeba Dictyostelium correlate with rat and human taste assays

“…These combined data suggest that bitter tastants are likely to act via a wide range of targets in mammals, in addition to the well-characterized TAS2 receptors. Pharmacogenetic studies in Dictyostelium (Williams, 2005), including for example the analysis of cell behavior in the absence of functional (used at comparable levels in several studies (Soto et al, 2015;Clapham et al, 2012) was more tolerable in the Dictyostelium model. With regard to the blind compounds tested, the rat and Dictyostelium models also showed similar responses, with all compounds showing a similar potency to within half a Log unit.…”

“…5A,B), suggesting that the model may be useful in this role. The in vivo rat BATA test, although widely accepted, has limitations including slow throughput, significant economic costs of testing and the use of animals (albeit a relatively small number per compound, typically 6-12 (Clapham et al, 2012; present study) and 10 in a more recent study using a novel analytical method aimed to improve the robustness of the rat BATA model (Soto et al, 2015), in a relatively benign regimen). Comparison of the responses of Dictyostelium and humans suggest a similar pattern of response, although fewer compounds were available to compare between the models.…”

New generalized poisson mixture model for bimodal count data with drug effect: An application to rodent brief‐access taste aversion experiments

“…BATA model is an emerging in vivo screening tool with great promise in providing taste assessment of drugs at an early stage of oral drug product design. The details of this experiment have been described previously . Briefly, 10 trained rats were tested in this study.…”

“…The details of this experiment have been described previously. 9 Briefly, 10 trained rats were tested in this study. After a 22-hour water-deprived period, each rat was placed in the lickometer and was presented randomly with different sipper tubes containing either deionized water or one of the six concentrations of a bitter drug, quinine hydrochloride dihydrate.…”