(M1130-04-24) The Impact of Cyclodextrin on Fasting and Fed Bioequivalence Studies in Solid Oral Immediate-Release Drug Products

Purpose: Betacyclodextrin (β-CD), or betadex, a common 7-glucose subunit ring of cyclodextrin (CD), is gaining presence as an excipient in solid oral immediate release (IR) drug products. β-CD is reported to potentially impact the drug pharmacokinetic (PK) behavior, which can subsequently impact bioequivalence (BE) outcomes between products. This study aimed to examine whether cyclodextrin may impact in vivo drug bioavailability or BE differently under fasting and fed conditions.

Methods: We collected all U.S Food and Drug Administration (FDA) approved New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) (generics) for solid oral IR drug products containing β-CD as an excipient. These applications included both fasting and fed PK or BE studies were subject for further analysis. Drug product formulation composition, fasting and fed PK BE data, and in vitro dissolution data were collected and analyzed.

Results: A total of 12 unique active pharmaceutical ingredients (APIs) containing β-CD were identified in FDA approved oral drug products (NDAs or reference listed drugs, RLDs). Of these, there are 5 unique APIs among 7 different applications (NDAs and ANDAs) approved for solid, oral IR products containing both fasting and fed PK studies. β-CD was utilized as an API stabilizer, diluent, or taste masking agent in all 7 applications. These APIs have diverse solubility and permeability properties ranging from Biopharmaceutical Classification System (BCS) Class Drugs I, II, and III. For API 1, the RLD utilizes the β-CD to stabilize the API by forming an API and β-CD complex. However, none of the 12 approved ANDAs referencing this RLD used β-CD in formulations. In APIs 2, 3, and 4, one ANDA for each API included β-CD as a diluent/filler, while all other combined 55 ANDA and NDA applicants did not. Lastly, for API 5, a chewable tablet, the RLD holder and two additionally approved ANDA applicants used β-CD as a taste masking agent, while the other three ANDA holders substituted β-CD with other taste masking agents. Overall, all the approved generic drug products established BE by meeting the 80% to 125% limits under both fasting and fed conditions. For the same API, there was no significant difference in PK parameters between formulations with and without β-CD. There was no impact of β-CD on in vitro dissolution profiles, as all ANDA applications had comparable dissolution profiles to their respective RLDs at recommended conditions; single-point dissolution tests with 85% dissolved in 30-minutes for BCS Class I and III drug products, and a two-point dissolution test for BCS Class II drug products.

Conclusion: Of all applications containing β-CD approved by U.S. FDA, β-CD did not pose impact on the PK behavior differently of BCS Class I, II, III drugs or affecting BE under both fasting and fed conditions.  Future work may be needed to determine if other types of CD or excipients affect PK behavior or affect BE under either fasting or fed conditions.

References: Rajeswari Challa, Alka Ahuja, Javed Ali, and R.K. Khar. Cyclodextrins in Drug Delivery: An Updated Review. AAPS PharmSciTech 2005; 6(2) Article 43.

Acknowledgments: The contents in this poster reflect the views of the authors and should not be construed to represent U.S. FDA’s views or policies. Specific API names and application numbers were not disclosed due to confidentiality reasons. However, masking API names would not affect the conclusions we draw on the potential impact of β-CD on PK or BE under fasting or fed conditions for these oral dosage form products.