In the study of human bioequivalence (BE), newly developed oral products sometimes fail to prove BE with a reference product due to the high variability in pharmacokinetic (PK) parameters after oral absorption. In this study, risk factors that incur bioinequivalence in BE study were analyzed by applying the Biopharmaceutics Classification System (BCS). Forty-four generic products were selected from a database of BE studies in the past 10 years at Towa Pharmaceutical Co., Ltd. (Osaka, Japan), and 90% confidence interval (CI) of AUC and C(max) in human BE study for all products were converted into coefficient of variation (CV(90)). Then, the required number of subjects to confirm BE was estimated from the 90% CI in human BE study of new products. It was found that both the permeability of drugs to human intestinal membrane (P(eff)) and the dose number calculated from their water solubility did not correlate well to CV(90) and the estimated subject number in human BE study, suggesting the contribution of other factors to cause the variability in oral drug absorption. As the PK parameter of drugs, the value of AUC/dose was calculated and plotted against CV(90) and the estimated subject number by classifying drugs into 4 BCS classes. For drugs in classes 1 and 3, AUC/dose gave a clear criterion to distinguish the drugs with a high risk of bioinequivalence, where drugs with low AUC/dose showed high CV(90) and large number of subjects. It was suggested that the high metabolic clearance (for class 1 drug) and low oral absorption (for class 3 drug) could be significant factors to incur bioinequivalence in human BE study, although for drugs in classes 2 and 4, clear factors were not defined. Consequently, for drugs in BCS classes 1 and 3, risks in human BE study to incur bioinequivalence could be predicted by calculating the AUC/dose. In the case of generic drugs, since the parameter of AUC/dose is available before initiating human BE study, this finding is expected to promote an efficient and cost-saving strategy for the development of oral drug products.
This study provided valuable information on intragastric fluid dynamics and gastric drug absorption in humans to establish a better in vitro-in vivo correlation in oral drug absorption.
The present study was aimed to predict the absorption profile of a risperidone immediate release tablet (IR) and to develop the level A in vitro-in vivo correlation (IVIVC) of the drug using the gastrointestinal simulation based on the advanced compartmental absorption and transit model implemented in GastroPlus™. Plasma concentration data, physicochemical, and pharmacokinetic properties of the drug were used in building its absorption profile in the gastrointestinal tract. Since the fraction absorbed of risperidone in simulation was more than 90% with low water solubility, the drug met the criteria of class II of the Biopharmaceutics Classification System. The IVIVC was developed based on the model built using the plasma data and the in vitro dissolution data in several dissolution media based on the Japanese Guideline for Bioequivalence Studies of Generic Products. The gastrointestinal absorption profile of risperidone was successfully predicted. A level A IVIVC was also successfully developed in all dissolution media with percent prediction error for Cmax and the area under the curve less than 10% for both reference and test drug.
MutS protein binds to DNA and specifically recognizes mismatched or small looped out heteroduplex DNA. In order to elucidate its structure-function relationships, the domain structure of Thermus thermophilus MutS protein was studied by performing denaturation experiments and limited proteolysis. The former suggested that T. thermophilus MutS consists of at least three domains with estimated stabilities of 12.3, 22.9 and 30.7 kcal/mol and the latter revealed that it consists of four domains: A1 (N-terminus to residue 130), A2 (131-274), B (275-570) and C (571 to C-terminus). A gel retardation assay indicated that T.thermophilus MutS interacts non-specifically with double-stranded (ds), but not single-stranded DNA. Among the proteolytic fragments, the B domain bound to dsDNA. On the basis of these results we have proposed the domain organization of T. thermophilus MutS and putative roles of these domains.
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