title: In vitro bioequivalence approach for a locally acting gastrointestinal drug: lanthanum carbonate.
abstract: A conventional human pharmacokinetic (PK) in vivo study is often considered as the "gold standard" to determine bioequivalence (BE) of drug products. However, this BE approach is not always applicable to the products not intended to be delivered into the systemic circulation. For locally acting gastrointestinal (GI) products, well designed in vitro approaches might be more practical in that they are able not only to qualitatively predict the presence of the active substance at the site of action but also to specifically assess the performance of the active substance. For example, lanthanum carbonate chewable tablet, a locally acting GI phosphate binder when orally administrated, can release free lanthanum ions in the acid environment of the upper GI tract. The lanthanum ions directly reach the site of action to bind with dietary phosphate released from food to form highly insoluble lanthanum-phosphate complexes. This prevents the absorption of phosphate consequently reducing the serum phosphate. Thus, using a conventional PK approach to demonstrate BE is meaningless since plasma levels are not relevant for local efficacy in the GI tract. Additionally the bioavailability of lanthanum carbonate is less than 0.002%, and therefore, the PK approach is not feasible. Therefore, an alternative assessment method is required. This paper presents an in vitro approach that can be used in lieu of PK or clinical studies to determine the BE of lanthanum carbonate chewable tablets. It is hoped that this information can be used to finalize an in vitro guidance for BE studies of lanthanum carbonate chewable tablets as well as to assist with "in vivo" biowaiver decision making. The scientific information might be useful to the pharmaceutical industry for the purpose of planning and designing future BE studies.
authors.affiliation: Division of Product Quality Research, Office of Pharmaceutical Science, Food and Drug Administration, Life Science Building 64, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, United States. Yongsheng.Yang@fda.hhs.gov
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Yang
authors.forename: Rakhi B
authors.initials: RB
authors.lastname: Shah
authors.forename: Lawrence X
authors.initials: LX
authors.lastname: Yu
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D005765:Gastrointestinal Agents / Q000493:pharmacokinetics*; D006801:Humans; D007700:Kinetics; D007811:Lanthanum / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency
chemical_list: D005765:Gastrointestinal Agents; C119467:lanthanum carbonate; D007811:Lanthanum