Orodispersible films (ODFs) possess potential to facilitate oral drug delivery to children; however, documentation of their acceptability in this age group is lacking. This study is the first to explore the initial perceptions, acceptability and ease of use of ODFs for infants and preschool children, and their caregivers through observed administration of the type of dosage form. Placebo ODFs were administered to children stratified into aged 6 to 12 months, 1 year, 2 years, 3 years, 4 years and 5 years old and into those with an acute illness or long-term stable condition in hospital setting. Acceptability of the dosage form and end-user views were assessed by (a) direct observation of administration, (b) questionnaires to caregivers and nurses, and (c) age-adapted questionnaires for children aged 3 years and over. The majority of children (78%) aged 3 years and over gave the ODF a positive rating both on verbal and non-verbal scales. Despite little prior experience, 78% of caregivers expressed positive opinion about ODFs before administration. After the ODFs were taken, 79% of infant caregivers and 86% caregivers of preschool children positively rated their child's acceptance of the ODF. The intraclass correlation coefficient value was 0.92 showing good agreement between ratings of caregivers and nurses. ODFs showed a high degree of acceptability among young children and their caregivers. If drug loading permits, pharmaceutical companies should consider developing pediatric medicines in this format. The methodology described here is useful in assessing the acceptability of active ODF preparations and other dosage forms to children.

The amount of drug remaining after previous doses, or drug accumulation, is closely related to drug efficacy and safety. An accurate calculation of the accumulation index or ratio (Rac) is crucial for dose finding. However, in drug accumulation studies little consensus exists with regard to experimental design or data analysis. We conducted a systematic review of the literature to produce a detailed profile of drug accumulation studies of the last 30 years (1980-2011). Ninety-six articles comprising 122 studies were analyzed. A typical drug accumulation study enrolled 10 to 20 subjects randomly assigned into treatment groups of 1 or 2 dose levels to observe pharmacokinetic behaviors. The median washout period between single and multiple dosing was 7 days, and the dose interval was 1-2 elimination half-lives in non- or one-compartmental models. Generally, the number of repeated times of administration for multiple dosing was 7-14, and the median number of sampling time points was 11. Eight different methods were used to calculate Rac. The most frequently used method, in 72.9% of the studies, was to set Rac equal to the ratio of the area under a plasma concentration-time curve (AUC) during a dosage interval at steady state to the AUC of a dosage interval after the first dose, i.e., Rac = AUC0-ι,ss / AUC0-ι,1. The values of Rac in the included studies ranged from 0.85 to 18.8, and 68.03% were <2. We suggest that sample size estimation for an accumulation study should be similar to that of a bioequivalence study, and in most studies, 18-24 subjects will be needed. Appropriate calculation methods for Rac should be selected based on the experimental design and data characteristics. The crucial values for non-, weak, moderate, and strong accumulation can be set at Rac < 1.2, 1.2 ≤ Rac < 2, 2 ≤ Rac < 5, and Rac ≥ 5, respectively. Accumulations studies should also give more regard to drug metabolism and increased accumulation in kidney or liver damaged patients.

The 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 with 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. IC50, 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 IC50s without symmetric assumption. The IC50 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 IC50 of 0.0502 mM (95% CI 0.0267-0.0859) was acquired with the lick ratios. Except one published model, the IC50 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". IC50s obtained with these two types of datasets showed similarity among all models thereby justified the robustness of the new E(max) model.

Taste is crucial for patient acceptability and compliance with prescribed medicines, in particular with pediatric patients. Evaluating the taste of new active pharmaceutical ingredients (APIs) is therefore essential to put in place adequate taste-masking techniques, if needed, which will lead to acceptable palatable formulations. Thus, there is an urgent need to develop and optimize taste assessment methods that could be used at different stages of the drug development process. The aim of this study was to investigate the suitability of the rat brief-access taste aversion (BATA) model as a screening tool for assessment of APIs aversiveness that could predict human taste responses. Presently, the taste intensity of nine marketed APIs known to have different levels of bitter intensity (quinine hydrochloride dihydrate, 6-n-propylthiouracil, sildenafil citrate, diclofenac sodium, ranitidine hydrochloride, caffeine citrate, isoniazid, telbivudine and paracetamol) was investigated at different overlapping concentrations with two in vivo taste assessment methods: the rat BATA model and human taste panels with the intention of determining the drugs' concentrations to produce half of the maximal rating. Overall there was a strong correlation (R-2 = 0.896) between rats IC50 and humans EC50 values. This correlation verifies the BATA model as a rapid and reliable tool for quantitative assessment of API aversiveness. A comparable ranking order was obtained mainly for high and medium aversive compounds, whereas it was less aligned for weakly aversive compounds. It was nonetheless possible to propose a classification of poor taste intensity determined in rats that would predict human taste tolerability.