UNASSIGNED: In this study, the data of 113 @entity1 bioequivalence (BE) studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time-concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (Peff). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low Peff might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of Peff/Do (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (Peff/Do < 0.149 * 10(-4) cm/s) showed high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by @entity5322 while intersubject variability was high for drugs metabolized by @entity5320 . For @entity5322 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of @entity1 BE study, low permeability, solubility-limited absorption, and high affinity to @entity5322 are identified as risk factors for high intrasubject variability in oral drug absorption. This information is of importance to design the @entity1 BE study for oral drug products containing APIs with a risk of large intrasubject variability in oral absorption.

Analysis of Intra- and Intersubject Variability in Oral Drug Absorption in XXXX Bioequivalence Studies of 131 Generic Products.

@entity1 :: ('9606', 'Species') :: ['human'] @entity5320 :: ('1565', 'Gene') :: ['CYP2D6'] @entity5322 :: ('1576', 'Gene') :: ['CYP3A4']
@entity1 :: (9606,Species) :: ['Human']
