Analysis of Risk Factors in Human Bioequivalence Study That Incur Bioinequivalence of Oral Drug Products

Abstract

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.

Assessing the performance of amorphous solid dispersions

“…88,[116][117][118][119] In Table 7 we have summarized several of the rate-determining physiological factors that influence the clinical performance of an amorphous dispersion that require greater consideration in preclinical testing. Central to amorphous solid dispersion performance will be the extent to which a variety of factors influence both the extent of supersaturation and permeability in the GI tract.…”

“…137 It is recommended that careful consideration be given to the permeability/absorption model used to classify a compound because cell lines and tissue sections may offer different confounding variables, which can lead to different results and confuse early in vivo studies. 119 The recently proposed Developability Classification System offers an opportunity to expand upon the BCS, and potentially the BDDCS. This system incorporates important factors that influence drug performance including the measurement of intestinal permeability and solubility in the context of formulation composition and its characteristics such as particle size.…”

Prediction of Solubility and Permeability Class Membership: Provisional BCS Classification of the World’s Top Oral Drugs

“…If the in vitro dissolution of a class III drug product is rapid under all physiological pH conditions, its in vivo behavior will essentially be similar to oral solution (controlled by gastric emptying), and as long as the drug product does not contain permeability modifying agents (this potential effect is largely mitigated by the large gastric dilution), in vitro dissolution test can ensure BE. Hence, biowaivers for BCS class III drugs are scientifically justified and have been recommended (20)(21)(22)(23)(24).…”

Biopharmaceutics classification system: importance and inclusion in biowaiver guidance

“…For example, while the United States (FDA, 2000), the European Union (EMEA, 2008), Brazil (Brasil, 2011) andWHO (2006) allow biowaiver based on dissolution and classification by BCS, Japan does not allow it (Yamashita, Tachiki, 2008). At this point, the FDA's and EMA´s guide and the proposed requirements by WHO for biowaiver also show discrepancies in the definitions of high solubility (pH of 7.5 in the FDA's guide and 6.8 in EMA's guide and WHO proposal) and high permeability (the criterion of 90% on FDA's guide and 85% in the WHO proposal and EMA's guide) (Ramirez et al, 2010).…”