This represents more than three or two times, respectively, the required amount of time to conduct a simple crossover study. this website Therefore, by increasing the duration of the study and the

number of dosing periods, replicate designs normally exhibit a higher dropout rate, which impacts negatively on the required sample size. The issue with the higher dropout rates is evident by analysing the bibliographic references, which shows 15.8 and 12.5 % dropout rates for full replicate studies [6, 7], while, according to our experience, we achieved a dropout rate of 7.2 % for this partial replicate TSA HDAC mw study and a 4.2 % dropout rate in a pilot crossover study (data on file). So, in trying to achieve a compromise between an extended duration of the clinical phase and reducing the sample size without much impact

from the dropout rate, we decided to conduct this study as a partial replicate design with three periods, including two administrations of the reference formulation in each sequence. This turned out to be a favourable decision since, according to the guidelines [4], the replicate design allowed for the scaled bioequivalence approach for C max and the duration of the clinical phase was contained and acceptable (37 days as opposed to the required 54 days in a four-period full replicate design), which led Cell Cycle inhibitor to a dropout rate lower than the one observed for full replicate studies. Further to this, the results of the study demonstrated that the within-subject variability for C max of the reference formulation was more than 30 % and this value was not the result of the presence of

outliers. However, it is important to point out that a replicate design may not be the solution if high within-subject variability is observed for the AUC parameter, which was not the case for ibandronic acid, since the bioequivalence guideline does not allow for the widening of intervals for that pharmacokinetic parameter [4]. The treatment periods should be separated by a washout period of at least five T ½ el in order to guarantee that the drug concentrations are below the lower limit of quantification at the beginning of each period [4]. In this study, the treatment periods were separated by a washout the of 14 days. When reviewing the published data on ibandronic acid pharmacokinetic properties, the authors noticed that the published half-life of ibandronic acid ranges from 10 to 60 hours [1] and, in one study in postmenopausal women that received a single oral dose of ibandronic acid150 mg, a mean T ½ el of 72 hours was observed [8]. In the current study, the T ½ el of ibandronic acid was approximately 10 hours for both formulations, which is in line with published studies but also in the lower limit of the range of values published.