(M0930-01-01) A Retrospective Analysis of Pharmacokinetic Variability between Fasting and Fasting-Sprinkle Bioequivalence Studies of Generic Modified-Release Drug Products: A Case Study on Esomeprazole Magnesium

Purpose: Patients with dysphagia (most prevalent in the elderly and children) experience difficulties in swallowing and a high risk of choking while taking capsules and tablets. This condition encouraged the development of novel methods of administration, including sprinkle formulations where drug-loaded pellets or granules are mixed with soft food (e.g., applesauce, pudding, or yogurt) upon administration.

To support generic drug approval of modified-release (MR) products with sprinkle formulations, a fasting-sprinkle bioequivalence (FSBE) study may be recommended in addition to a fasting BE (FBE) study. For proper BE assessment of generic MR products with sprinkle administration option, we need to understand the key factors to determine when an FSBE study is needed. One of these factors is the pharmacokinetic (PK) variability under a fasting-sprinkle condition. To assess this, an estimated within-subject variability (E-WSV) was compared in FBE and FSBE studies of MR products submitted to the FDA. A case study of esomeprazole magnesium delayed-release capsule pellets is presented.

Methods: A list of approved abbreviated new drug applications (ANDAs) of esomeprazole magnesium with sprinkle administration option in labeling was collected. Subsequently, FBE and FSBE studies were retrieved from these ANDAs. For each ANDA, a non-compartmental analysis and BE analysis of PK metrics (AUCt, AUC0-inf, and Cmax) followed by E-WSV calculation of PK metrics was performed using Phoenix WinNolin 8.3 (Certara, Princeton, NJ, USA). Additional factor, include formulation variation, study design, and number of subjects were evaluated.

Results: Nineteen approved ANDAs of esomeprazole magnesium conducted FBE and FSBE (using applesauce) studies. The average E-WSV for PK metrics (AUCt, AUC0-inf, and Cmax) was < 30% in FBE and FSBE. Esomeprazole magnesium reference listed drug (RLD) and all respective ANDAs used the same control releasing excipient. The difference (w/w %) of control releasing excipient between the RLD and all respective ANDAs was similar except for four ANDAs. For the selected four ANDAs, two ANDAs showed no difference in E-WSV (FBE vs. FSBE), however, the other two ANDAs showed a higher E-WSV in FBE vs. FSBE, most likely due to a difference in the number of subjects ( >5 subjects).

Conclusion: The average E-WSV of esomeprazole magnesium ANDAs was not significantly different in FBE vs. FSBE. Lack of significant difference in E-WSV for PK metrics suggests that rate and extent of exposure are similar when esomeprazole magnesium administered as an intact capsule or sprinkled in soft food. Further studies are ongoing for all MR products with sprinkle administration option. Overall, these findings may inform our future research on the need for FSBE study of generic MR products.

Acknowledgements:This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies. Dr. Abdallah and Gabal were supported by an appointment to the research participation program at CDER, administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between U.S. Department of Energy and the FDA.